Nitrile derivatives that inhibit cathepsin K

ABSTRACT

Compounds of the formula:  
                 
 
     wherein R 1  to R 7  and Y are as defined in the specification, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof, are useful for treating diseases associated with cystein proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease.

BACKGROUND OF THE INVENTION

[0001] 1. Field

[0002] The present invention relates to novel nitrile derivatives, theirmanufacture and use as medicaments. In particular, the invention relatesto novel nitrile derivatives of formula (I)

[0003] 2. Description

[0004] Cysteine proteases have been viewed as lysosomal mediators ofterminal protein degradation. Several newly discovered members of thisenzyme class, however, are regulated proteases with limited tissueexpression, which implies specific roles in cellular physiology and thuswould allow a specific targeting of these activities without interferingwith the general lysosomal protein degragation. Development ofinhibitors of specific cysteine proteases promises to provide new drugsfor modifying immunity, osteoporosis, neurodegeneration, chronicinflammation, cancer and malaria (Brömme, Drug News Perspect 1999,12(2), 73-82; Chapman et al., Annu. Rev. Phys. 1997, 59, 63-88).

[0005] Cysteine proteases can be grouped into two superfamilies: thefamily of enzymes related to interleukin 1β converting enzyme (ICE), andthe papain superfamily of cysteine proteases. Presently there are atleast 12 human proteases of the papain family from which sequences havebeen obtained (cathepsin B, L, H, S, O, K, C, W, F, V(L2), Z(X) andbleomycin hydrolase). Cathepsin K was first discovered as a cDNAprominent in rabbit osteoclasts and referred to as OC-2 (Tezuka et al.,J. Biol. Chem. 1994, 269, 1106-1109). Recent observations indicate thatcathepsin K is a very potent mammalian elastase. Cathepsin K, as well ascathepsins S and L, are also potent collagenases and gelatinases.Macrophages appear capable of mobilizing the active proteases withinendosomal and/or lysosomal compartments to the cell surface underspecial circumstances. In this case, the cell surface/substrateinterface becomes a compartment from which endogenous inhibitors areexcluded and can be viewed as a physiological extension of the lysosome.This type of physiology is an innate trait of osteoclasts, a bonemacrophage, and may also be exploited by other macrophages or cells inthe context of inflammation. The abundance of cathepsin K in osteoclastssuggests that cathepsin K plays an important role in bone resorption.Studies revealed that cathepsin K is the predominant cysteine proteasein osteoclasts and is specifically expressed in human osteoclasts. Acorrelation between inhibition of cysteine protease activity and boneresorption has been reported (Lerner et al., J. Bone Min. Res. 1992, 7,433; Everts et al., J. Cell. Physiol. 1992, 150, 221). Cathepsin K hasbeen detected in synovial fibroblasts of RA patients, as well as inmouse hypertrophic chondrocytes (Hummel et al., J. Rheumatol. 1998,25(10), 1887-1894.). Both results indicate a direct role of cathepsin Kin cartilage erosion. P. Libby (Libby et al., J. Clin. Invest. 1998, 102(3), 576-583) reported that normal arteries contain little or nocathepsin K or S whereas macrophages in atheroma contained abundantimmunoreactive cathepsins K and S. Most of the elastolytic activity oftissue extracts associated with human atheroma compared tonon-atherosclerotic arteries could be inhibited with E64, anon-selective cysteine protease inhibitor.

[0006] Tumor progression and metastasis are characterized by theinvasion of tumors into adjacent tissues as well as by the dissociationof cancer cells from primary tumors and the infiltration of metastaticcells into organs. These processes are associated with the degragationof extracellular matrix proteins and thus require proteolytic activity.Cathepsin K has been identified in primary breast tumors, as well as inbreast tumor-derived bone metastasis (Littlewood-Evans et al., CancerRes. 1997, 57, 5386-5390).

[0007] Different classes of compounds, such as aldehydes, α-ketocarbonylcompounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methylketones, ketomethylsulfonium salts, epoxy succinyl compounds, vinylsulfones, aminoketones, and hydrazides have been identified as cysteineprotease inhibitors (Schirmeister et al., Chem. Rev. 1997, 97, 133-171;Veber et al., Proc. Natl. Acad. Sci. USA 1997, 94, 14249-14254). Theshortcomings these compounds suffer from include lack of selectivity,poor solubility, rapid plasma clearance and cytotoxicity. A needtherefore exists for novel inhibitors useful in treating diseases causedby pathological levels of proteases, such as cysteine proteases,including cathepsins, and especially cathepsin K. Therefore, a needexists for compounds that are selective inhibitors of cathepsin K.

SUMMARY OF THE INVENTION

[0008] The subject invention provides compounds of the formula:

[0009] wherein

[0010] Y is O, S, or CH—R²;

[0011] R¹ and R³ are each independently hydrogen or methyl and R² ishydrogen, or R¹ is hydrogen and R² and R³ together are —CH₂— thusforming a cyclopropyl ring;

[0012] R⁴, R⁵ are each independently hydrogen or lower-alkyl;

[0013] R⁶ is cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, orheteroaryl-lower-alkyl;

[0014] R⁷ is —CO—R^(a), —SO₂—R^(b) or —CS—NH—R^(c), wherein

[0015] R^(a) is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl,aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl,arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R^(d)—NH,

[0016] R^(b) is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl,heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,

[0017] R^(c) is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl,heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,

[0018] R^(d) is aryl-lower-alkyl;

[0019] or a pharmaceutically acceptable salt or ester thereof.

[0020] A preferred group of compounds are of the formula:

[0021] wherein Y, R¹, R³, R⁴, R⁵, R⁶ and R⁷ are as defined above.

[0022] Another favored group of compounds are of the formula:

[0023] wherein

[0024] R^(6′)is aryl;

[0025] R^(7′)is —CO—R^(a′)or —CS—NH—R^(c′), wherein

[0026] R^(a′)is cycloalkyl-lower-alkyl, aryl-lower-alkyl,aryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl,and

[0027] R^(c′) is heteroaryl-lower-alkyl;

[0028] or a pharmaceutically acceptable salt or ester thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The subject invention will now be described in terms of itspreferred embodiments. These embodiments are set forth to aid inunderstanding the invention but are not to be construed as limiting.

[0030] The present invention also relates to processes for thepreparation of the compounds of formula (I).

[0031] wherein

[0032] Y represents O, S, or CH—R,

[0033] R¹ and R³ independently from each other represent hydrogen ormethyl and R² represents hydrogen, or R¹ represents hydrogen and R² andR³ together are —CH₂— to form a cyclopropyl ring,

[0034] R⁴, R⁵ independently from each other represent hydrogen orlower-alkyl,

[0035] R⁶ represents cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, orheteroaryl-lower-alkyl,

[0036] R⁷ represents —CO—R^(a), —SO₂—R^(b) or —CS—NH—R^(c), wherein

[0037] R^(a) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl,aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl,arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R^(d)—NH,

[0038] R^(b) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,

[0039] R^(c) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,

[0040] R^(d) represents aryl-lower-alkyl,

[0041] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

[0042] The nitriles derivatives of the present invention have aninhibitory activity on cysteine proteases, more paticulary on cysteineproteases of the papain superfamily, even more paticularly on cysteineproteases of the cathepsin family, most particularly on cathepsin K. Itwas surprisingly found, that this inhibiting effect on cathepsin K isselective with respect to other cathepsins. While compounds of formula(I) very efficiently inhibit cathepsin K, the inhibition of otherprotease inhibitors such as cathepsin S, cathepsin L and cathepsin B ismuch weaker. Therefore the new compounds of formula (I) are usefull forspecifically inhibiting cathepsin K. They can accordingly be used forthe treatment of disorders which are associated with cysteine proteasessuch as osteoporosis, osteoarthritis, rheumatoid arthritis, tumormetastasis, glomerulonephritis, atherosclerosis, myocardial infarction,angina pectoris, instable angina pectoris, stroke, plaque rupture,transient ischemic attacks, amaurosis fugax, peripheral arterialocclusive disease, restenosis after angioplasty and stent placement,abdominal aortic aneurysm formation, inflammation, autoimmune disease,malaria, ocular fundus tissue cytopathy and respiratory disease.Accordingly, the present invention relates to a method for theprophylactic and/or therapeutic treatment of diseases which areassociated with cystein proteases such as osteoporosis, osteoarthritis,rheumatoid arthritis, tumor metastasis, glomerulonephritis,atherosclerosis, myocardial infarction, angina pectoris, instable anginapectoris, stroke, plaque rupture, transient ischemic attacks, amaurosisfugax, peripheral arterial occlusive disease, restenosis afterangioplasty and stent placement, abdominal aortic aneurysm formation,inflammation, autoimmune disease, malaria, ocular fundus tissuecytopathy and respiratory disease, which method comprises administeringa compound of formula (I) to a human being or an animal. The presentinvention also relates to pharmaceutical compositions comprising acompound of formula (I) and a pharmaceutically acceptable carrier and/oradjuvant. Furthermore, the present invention relates to the use of suchcompounds for the preparation of medicaments for the treatment ofdisorders which are associated with cystein proteases.

[0043] Unless otherwise indicated the following definitions are setforth to illustrate and define the meaning and scope of the variousterms used to describe the invention herein.

[0044] In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

[0045] The term “alkyl” refers to a branched or straight chainmonovalent saturated aliphatic hydrocarbon radical of one to twentycarbon atoms, preferably one to sixteen carbon atoms.

[0046] The term “lower-alkyl” refers to a branched or straight chainmonovalent alkyl radical of one to seven carbon atoms, preferably one tofour carbon atoms. This term is further exemplified by such radicals asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and thelike.

[0047] The term “cycloalkyl” refers to a monovalent carbocyclic radicalof 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms.

[0048] The term “halogen” refers to fluorine, chlorine, bromine andiodine, with fluorine, chlorine and bromine being preferred and chlorineand bromine being more preferred.

[0049] The term “alkoxy” refers to the group R′—O—, wherein R′ is analkyl. The term “lower-alkoxy” refers to the group R′—O—, wherein R′ isa lower-alkyl.

[0050] The term “aryl” relates to the phenyl or naphthyl group which canoptionally be mono- or multiply-substituted by alkyl, halogen, hydroxy,alkoxy, —O—(CH₂)₁₋₇—O—, aryloxy, or arylalkoxy. Substitution in meta- orin meta- and para-position is preferred. Preferred substituents arelower-alkyl, fluorine, chlorine, bromine, lower-alkoxy, methylenedioxy,and aryl-lower-alkoxy. More preferred substituents are chlorine,bromine, methoxy, and benzyloxy. Another preferred substituted phenylgroup is the benzo[1,3]dioxol-5-yl group.

[0051] The term “heteroaryl” refers to an aromatic 5- or 6-membered ringwhich can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphursuch as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, with furyl and thienyl beingpreferred. The term “heteroaryl” further refers to bicyclicheteroaromatic ring systems such as e.g. indolyl. A heteroaryl group mayhave a substitution pattern as described earlier in connection with theterm “aryl”.

[0052] An aryl-lower-alkyl group may optionally comprise a second arylgroup, e.g. a phenyl group, at the lower-alkyl moiety.

[0053] The term “aryloxy” relates to a group aryl-O—. The term“arylthio” relates to a group aryl-S—.

[0054] The term “pharmaceutically acceptable salts” embraces salts ofthe compounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonicacid and the like, which are non toxic to living organisms.

[0055] The term “pharmaceutically acceptable esters” embraces esters ofthe compounds of formula (1), in which hydroxy groups have beenconverted to the corresponding esters with inorganic or organic acidssuch as nitric acid, sulphuric acid, phosphoric acid, citric acid,formic acid, maleic acid, acetic acid, succinic acid, tartaric acid,methanesulphonic acid, p-toluenesulphonic acid and the like, which arenon toxic to living organisms.

[0056] In detail, the present invention refers to compounds of formula(I)

[0057] wherein

[0058] Y represents O, S, or CH—R²,

[0059] R¹ and R³ independently from each other represent hydrogen ormethyl and R² represents hydrogen, or R¹ represents hydrogen and R² andR³ together are —CH₂— to form a cyclopropyl ring,

[0060] R⁴, R⁵ independently from each other represent hydrogen orlower-alkyl,

[0061] R⁶ represents cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, orheteroaryl-lower-alkyl,

[0062] R⁷ represents —CO—R^(a), —SO₂—R^(b) or —CS—NH—R^(c), wherein

[0063] R^(a) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl,aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl,arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R^(d)—NH,

[0064] R^(b) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,

[0065] R^(c) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,

[0066] R^(d) represents aryl-lower-alkyl,

[0067] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

[0068] In a preferred embodiment, the present invention relates tocompounds as described above, wherein

[0069] R⁷ represents —CO—R^(a), —SO₂—R^(b) or —CS—NH—R^(c), wherein

[0070] R^(a) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl,aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, or R^(d)—NH,

[0071] R^(b) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,

[0072] R^(c) represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl,aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,

[0073] R^(d) represents aryl-lower-alkyl,

[0074] and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.

[0075] The compounds of formula (I) have at least 2 asymmetric carbonatoms and can exist in the form of optically pure enantiomers or asracemates. The invention embraces all of these forms. Preferredcompounds of formula (I) are compounds of formula (Ia) which are derivedfrom the corresponding S-proline derivatives.

[0076] wherein Y, R¹, R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, andpharmaceutically acceptable salts and/or pharmaceutically acceptableesters thereof.

[0077] Compounds of formula (I) in which Y represents CH—R² arepreferred, with those wherein R² is hydrogen being particularlypreferred. Compounds of formula (I) in which R¹, R³, R⁴ and/or R⁵represent hydrogen are also preferred. Another preferred embodiementrefers to compounds of formula (I) in which R⁶ is phenyl, furanyl,thiophenyl, or pyrrolyl, optionally substituted with alkyl, halogen,hydroxy, alkoxy, —O—(CH₂)₁₋₇—O—, aryloxy, or aryl-alkoxy. Further,compounds of formula (I) in which R⁶ represents phenyl, phenylsubstituted in meta-position, phenyl substituted in meta- and inpara-position or benzo[1,3]dioxol-5-yl are also preferred with3-methoxy-phenyl, 3,4-dimethoxy-phenyl, 4-benzyloxy-3-methoxy-phenyl,3-chloro-phenyl, 3-bromo-phenyl, or benzo[1,3]dioxol-5-yl beingespecially preferred.

[0078] Compounds of formula (I) in which R⁷ represents —CO—R^(a) andR^(a) is as defined above are preferred. Compounds of formula (I) inwhich R⁷ represents —CO—R^(a) and R^(a) is benzyloxy,cyclopentyl-ethylene, or benzyloxy-methylene are especially preferred.Further, compounds of formula (I) in which R⁷ represents —CO—R^(a) andR^(a) is 3-bromobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl,or 2-methyl-phenyloxymethylene are also especially preferred. A furtherpreferred embodiement are compounds of formula (I) in which R⁷represents —CS— NH—R^(c) and R^(c) is as defined above. Compounds offormula (I) in which R⁷ represents —CS—NH— R^(c) and R^(c) is benzyl,3-fluorobenzyl, or furan-2-yl-methylene are especially preferred.Another preferred embodiement relates to compounds of formula (I),wherein R⁷ represents —SO₂—R^(b) and R^(b) is as defined above, withthose in which R^(b) is naphthyl being particularly preferred.

[0079] Preferred compounds of formula 1 are

[0080] (1RS,2RS,5SR)-2-{[(RS)- or-[(SR)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester,

[0081](S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylicacid benzyl ester,

[0082](S)-2-[(S)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylicacid benzyl ester,

[0083] (S)-1-(3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (R)- and(S)-(cyano-phenyl-methyl)-amide,

[0084] (S)-2-{(S)- and(R)-[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0085] (S)-2-{(S)- and(R)-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0086] (S)-2-[(R)- and(S)-(Cyano-cyclopropyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acidbenzyl ester,

[0087] (S)-2-[(R)- and(S)-(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-1-carboxylicacidbenzyl ester,

[0088] (R)-4-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-thiazolidine-3-carboxylicacid benzyl ester,

[0089] (2S,3R)-2-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl-pyrrolidine-1-carboxylicacid benzyl ester,

[0090] (S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,

[0091] (S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0092] (S)-1-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0093] (S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0094] (S)-1-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylicacid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0095] (S)-2-((R)- and(S)-1-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1-carboxylic acidbenzyl ester,

[0096] (R)-4-{(R)- and(S)-[(4-Chloro-phenyl)-cyano-methyl]-carbamoyl}-thiazolidine-3-carboxylicacid benzyl ester,

[0097] (S)-2-{(R)- and(S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0098] (S)-2-[(R)- and(S)-(Cyano-o-tolyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acidbenzyl ester,

[0099] (S)-2-{(R)- and(S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0100] (S)-2-{(R)- and(S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0101] (S)-2-{(R)- and(S)-[Cyano-(3-fluoro-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0102] (S)-2-[(R)- and(S)-(Cyano-m-tolyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acidbenzyl ester,

[0103] (S)-2-{(R)- and(S)-[(4-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0104] (S)-2-{(R)- and(S)-[Cyano-(3,4,5-trimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0105] (S)-2-{(R)- and(S)-[Cyano-(3-phenoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0106] (S)-2-{(R)- and(S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0107] (S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0108] (S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid((R)- and (S)-benzo[ 1,3]dioxol-5-yl-cyano-methyl)-amide,

[0109] (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid((R)- and (S)-benzo[ 1,3]dioxol-5-yl-cyano-methyl)-amide,

[0110] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,

[0111](S)-1-(5-Dimethylamino-naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylicacid [(R)- and

[0112] (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0113] (S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0114] (S)-1-(Naphthalene-2-carbonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0115] (S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0116] (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0117] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0118] (S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0119] (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0120] (S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0121] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-chloro-phenyl)-cyano-methyl] -amide,

[0122] (S)-Pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and(S)-(3-chloro-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide],

[0123] (S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-bromo-phenyl)-cyano-methyl] -amide,

[0124] (S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-bromo-phenyl)-cyano-methyl] -amide,

[0125] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-bromo-phenyl)-cyano-methyl] -amide,

[0126] (S)-Pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and(S)-(3-bromo-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide],

[0127] (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3-methoxy-phenyl)-methyl] -amide,

[0128] (S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-methoxy-phenyl)-methyl] -amide,

[0129] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-methoxy-phenyl)-methyl] -amide,

[0130] 2-((R)- and(S)-1-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1-carboxylic acidbenzyl ester,

[0131] (S)-2-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0132] (S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid((R)- and (S)-benzo[ 1,3]dioxol-5-yl-cyano-methyl)-amide,

[0133] (S)-Pyrrolidine-1,2-dicarboxylic acid 2-{(R)- and(S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-amide}1-[(S)-(1-naphthalen-1-yl-ethyl)-amide],

[0134] (S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0135] and pharmaceutically acceptable esters thereof.

[0136] Other preferred compounds of formula 1 are

[0137] (S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0138] (S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0139] (S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0140] (S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0141] (S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0142] (S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0143] (S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0144] (S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0145] (S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0146] (S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0147] (S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0148] (S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0149] (S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0150] (S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0151] (S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0152] (S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0153] (S)-1-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0154] (S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0155] (S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0156] (S)-1-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0157] (S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0158] (S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0159] (S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0160] (S)-1-(3-Phenyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0161](S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[ 1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0162](S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0163] (S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0164](S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0165] (S)-1-(3-1H-Indol-3-yl-propanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0166] (S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0167] (S)-1-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0168] (S)-1-(4-Cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0169] (S)-1-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0170] (S)-1-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0171] (S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl)-amide,

[0172](S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0173] (S)-1-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0174] (S)-1-(1-Naphthalen-1-yl-methanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0175] (S)-1-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0176] (S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0177] (S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0178] (S)-1-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0179] (S)-1-(4-Cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0180](S)-1-{1-[1-(4-Chloro-phenyl)-cyclopentyl]-methanoyl}-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,

[0181] (S)-1-((Z)-3-Phenyl-allanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0182] (S)-1-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0183] (S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0184] (S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0185] (S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0186](S)-1-[2-(3,4,5-Trimethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0187] (S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0188] (S)-1-(1-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0189] (S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0190] (S)-1-[2-(4-Chloro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0191] (S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0192] (S)-1-(3,3-Diphenyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0193] (S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0194] (S)-1-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0195] (S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0196] (S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0197](S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[ 1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0198] (S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0199] (S)-1-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0200] (S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0201](S)-1-[3-(2,3,4-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0202] (S)-1-(2-Benzyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0203] (S)-1-(1-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0204] (S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro -phenyl)-1-cyano-methyl]-amide,(S)-1-(1-Cyclohexyl-methanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,(S)-1-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,(S)-1-[3-(3,4,5-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,

[0205] (S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3-phenoxy-phenyl)-methyl] -amide,

[0206] (S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0207] (S)-1-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0208] (S)-1-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0209] (S)-1-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide, and

[0210](S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide.

[0211] Especially preferred compounds of formula (I) are

[0212](S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylicacid benzyl ester,

[0213] (2S,3R)-2-{(R)- and(S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl-pyrrolidine-1-carboxylicacid benzyl ester,

[0214] (S)-2-[(R)- and(S)-(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-1-carboxylicacidbenzyl ester,

[0215] (S)-2-{(R)- and(S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0216] (S)-2-{(R)- and(S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester,

[0217] (S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,

[0218] (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid((R)- and (S)-benzo[ 1,3]dioxol-5-yl-cyano-methyl)-amide,

[0219] (S)-2-{(R)- and(S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester, and

[0220] (S)-1-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.

[0221] Other especially preferred compounds of formula (I) are

[0222] (S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0223] (S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0224] (S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0225] (S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl] -amide,

[0226] (S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,

[0227] (S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide,

[0228] (S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide, and

[0229] (S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.

[0230] Other especially preferred compounds of formula (I) are

[0231] (S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl] -amide, and

[0232] (S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.

[0233] The invention also relates to compounds of formula (IV)

[0234] wherein Y, R¹, R³, R⁴, R⁵ and R⁶ have the same significances asgiven for compounds of formula (I).

[0235] The invention also relates to the use of compounds as definedabove for the treatment or prophylaxis of diseases which are associatedwith cysteine proteases such as osteoporosis, osteoarthritis, rheumatoidarthritis, tumor metastasis, glomerulonephritis, atherosclerosis,myocardial infarction, angina pectoris, instable angina pectoris,stroke, plaque rupture, transient ischemic attacks, amaurosis fugax,peripheral arterial occlusive disease, restenosis after angioplasty andstent placement, abdominal aortic aneurysm formation, inflammation,autoimmune disease, malaria, ocular fundus tissue cytopathy andrespiratory disease. In a preferred embodiement, the invention relatesto the use of compounds as defined above for the treatment orprophylaxis of osteoporosis, instable angina pectoris or plaque rupture.

[0236] Further, the invention relates to compounds as defined above foruse as therapeutic active substances, in particular in context withdiseases which are associated with cysteine proteases such asosteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease. In a preferredembodiement, the invention relates to compounds as defined above for useas therapeutic active substances in context with osteoporosis, instableangina pectoris or plaque rupture.

[0237] The invention also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant, in particular for use in context with diseaseswhich are associated with cysteine proteases such as osteoporosis,osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease. In a preferredembodiement, the invention relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant for use in context with osteoporosis, instableangina pectoris or plaque rupture.

[0238] A further embodiment of the present invention refers to the useof compounds as defined above for the preparation of medicaments for thetreatment or prophylaxis of diseases which are associated with cysteinproteases such as osteoporosis, osteoarthritis, rheumatoid arthritis,tumor metastasis, glomerulonephritis, atherosclerosis, myocardialinfarction, angina pectoris, instable angina pectoris, stroke, plaquerupture, transient ischemic attacks, amaurosis fugax, peripheralarterial occlusive disease, restenosis after angioplasty and stentplacement, abdominal aortic aneurysm formation, inflammation, autoimmunedisease, malaria, ocular fundus tissue cytopathy and respiratorydisease. In a preferred embodiement, the invention relates to the use ofcompounds as defined above for the preparation of medicaments for thetreatment or prophylaxis of osteoporosis, instable angina pectoris orplaque rupture. Such medicaments comprise a compound as defined above.

[0239] An additional embodiment of the invention relates to a method forthe prophylactic and/or therapeutic treatment of disorders in whichcathepsin K plays a significant pathological role, such as osteoporosis,osteoarthritis, rheumatoid arthritis, tumor metastasis,glomerulonephritis, atherosclerosis, myocardial infarction, anginapectoris, instable angina pectoris, stroke, plaque rupture, transientischemic attacks, amaurosis fugax, peripheral arterial occlusivedisease, restenosis after angioplasty and stent placement, abdominalaortic aneurysm formation, inflammation, autoimmune disease, malaria,ocular fundus tissue cytopathy and respiratory disease, which methodcomprises administering a compound as defined above to a human being oran animal. A preferred embodiement of the invention relates to a methodfor the prophylactic and/or therapeutic treatment of osteoporosis,instable angina pectoris or plaque rupture, which method comprisesadministering a compound as defined above to a human being or an animal.

[0240] The invention further relates to a process for the manufacture ofcompounds of formula (I) which process comprises

[0241] a) reacting a compound of formula (II)

[0242] with a compound of formula (III)

[0243] wherein Y, R¹, R³, R⁵, R⁶ and R⁷ have the significances givenabove, or

[0244] b) reacting a compound of formula (IV)

[0245] with a compound of formula (V), (VI), (VII) or (VIII)

[0246] wherein Y, R¹, R³, R⁴, R⁵, R⁶, R^(a), , R^(b), R^(c) and R^(d)have the significances given above.

[0247] The invention also relates to a process as described above, whichprocess comprises the preparation of pharmaceutically acceptable saltsand/or pharmaceutically acceptable esters. The formation of the estersand/or salts can be carried out at different stages of the process, e.g.with the compound of formula (I) or with the corresponding startingmaterials.

[0248] The reaction of a compound of formula (II) with a compound offormula (III) can be carried out by methods known to the person skilledin the art. The reaction can conveniently be carried out by dissolvingcompound (II), compound (III), TPTU(O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′ ,N′-tetramethyluroniumtetrafluoroborate) and Hünigsbase (N-Ethyldiisopropylamine) in MeCN andstirring the mixture at room temperature for 6 to 16 hours. The reactionmixture can be concentrated and the product can be obtained by methodsknown to the person skilled in the art, e.g. by extraction and columnchromatography. Alternatively, a compound of formula (II) can bedissolved in CH₂Cl₂ and reacted for 6 to 16 hours at room temperaturewith a compound of formula (III) in the presence of N-methylmorpholin,HOBT and EDCI. The product can be obtained by, methods known per se,e.g. by extraction and HPLC.

[0249] The reaction of a compound of formula (IV) with a compound offormula (V), (VI), (VII) or (VIII) is conveniently carried out bypreparing a solution of compound (IV) in CH₂Cl₂ and adding a solution ofcompound (V), (VI) or (VII) in CH₂Cl₂. To this mixture, Triethylamin isadded and after shaking 6 to 16 hours at room temperature formic acid isadded. The product can be isolated and purified by methods known per se,e.g. by evaporation of the solvent and HPLC.

[0250] In order to prepare pharmaceutically acceptable salts and/orpharmaceutically acceptable esters of compounds of formula (I), it ispossible to prepare the corresponding esters and/or salts starting fromthe compounds of formula (I). It is also possible, to form the estersand/or salts at an earlier stage, e.g. to form the corresponding saltsan/or esters of the corresponding starting materials. The methods toprepare pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters as defined before are known in the art.

[0251] Compounds of formula (II) are prepared by methods already knownto the person skilled in the art. Conveniently, the corresponding aminoacid is converted to the corresponding methyl ester by reacting theamino acid in MeOH in the presence of thionylchloride. The resultingintermediate product is isolated by methods known per se, e.g. byextraction and evaporation of the solvent. The intermediate product islinked to the desired substituent R⁷ analogously to the method describedabove. The methyl ester is then saponified to yield a compound offormula (II) by dissolving the methyl ester and 2 N NaOH in MeOH andstirring the mixture 5 to 16 hours at room temperature. The resultingcompound (II) is isolated by methods known per se, e.g. by extractionand evaporation of the solvent.

[0252] Compounds of formula (III) can conveniently be obtained by addinga solution of the corresponding aldehyde in CH₂Cl₂ to a solution ofNH₄Cl and NaCN in H₂O and MeOH at 0° C. The mixture is stirred andallowed to warm to room temperature. After addition of NH₃ solution andcompletion of the reaction the resulting compound of formula (III) isisolated and purified by methods known to the person skilled in the art,e.g. by extraction. The corresponding hydrochlorid can be prepared bymethods known per se.

[0253] Chiral compounds of formula (III) can conveniently be obtained byadding ammonia to a mixed anhydride (prepared from a suitable t-BOCprotected amino acid and isobutylchloroformate) at −10° C. The reactionmixture is stirred at room temperature for 1-5 h. After completion ofthe reaction the resulting t-BOC protected amino acid amide is isolatedand purified by methods known to the person skilled in the art, e.g. byextraction. The Boc protected amino acid amide and triethylamine aredissolved in THF and trifluoroacetic acid anhydride at 0° C. The mixtureis stirred for 1-5 h at 0° C., then at room temperature for 1-2 h. Afterisolation and purification of the resulting intermediate product, e.g.by evaporation of the solvent and flash chromatography, the t-BOCprotective group can be cleaved off with HCl in acetic acid to yield thedesired compound of formula (III).

[0254] Compounds of formula (IV) can conveniently be obtained byreacting the corresponding t-BOC protected amino acid with a compound offormula (III) analogous to the method described above. After isolationand purification of the resulting intermediate product, e.g. byevaporation of the solvent and flash chromatography, the t-BOCprotective group can be cleaved off with trifluoro-acetic acid to yieldthe desired compound of formula (IV) with trifluoro-acetic acid.

[0255] Compounds of formula (V), (VI), (VII) and (VIII) are eithercommercially available or can be obtained by methods known in the art.

[0256] The present invention relates to all compounds of formula (I), asprepared by one of the processes described above.

[0257] The inhibitory activity of the compounds against cathepsin K, S,L and B was tested at room temperature in 96-wells opaque whitepolystyrene plates (Costar). The cathepsin K inhibitory activity wastested as follows:

[0258] 5 μl of an inhibitor diluted in 5 mM sodium phosphate, NaCl 15 mMpH 7.4 containing 1% DMSO (final concentrations: 10-0.0001 μM) werepreincubated for 10 min with 35 μl of human recombinant cathepsin K(final concentration: 1 nM) diluted in assay buffer (100 mM sodiumacetate pH 5.5 containing 5 mM EDTA and 20 mM cysteine). After additionof 10 μl of the fluorogenic substrate Z-Leu-Arg-MCA diluted in assaybuffer (final concentration: 5 μM), increase of fluorescence (excitationat 390 nm and emission at 460 nm) was measured for 7.5 min every 45 sec.The initial velocity (RFU/min) was derived from the linear fit of the 11reading points.

[0259] The cathepsin B inhibitory activity was assayed under the sameconditions as the cathepsin K inhibitory activity using human livercathepsin B (Calbiochem) at a final concentration of 1 nM.

[0260] The cathepsin L inhibitory activity was assayed under the sameconditions as the cathepsin K inhibitory activity using human livercathepsin L (Calbiochem) at a final concentration of 3 nM.

[0261] Cathepsin S inhibitory activity was assayed analogeously to thecathepsin K inhibitory activity, except that the buffer was 100 mMpotassium phosphate, 5 mM EDTA, 5 mM DTT (freshly added), 0.01% TritonX-100, pH 6.5 and the fluorogenic substrate was Z-Val-Val-Arg-MCA(Bachem) (final concentration: 20 μM). Human recombinant cathepsin S(Wiederanders et al., Eur. J. Biochem. 1997, 250, 745-750) was used at afinal concentration of 0.5 nM.

[0262] The results are given as IC₅₀ values which denote theconcentration of the inhibitor at which the enzymatic activity isinhibited by 50%. The IC₅₀ values are determined from a linearregression curve from a logit-log plot. Cathepsin K Cathepsin SCathepsin L Cathepsin B Compound no. IC₅₀ (μMol/l) IC₅₀ (μMol/l) IC₅₀(μMol/l) IC₅₀ (Mol/l) (Example 10)  2 0.046 >10 >10 2.8 11 0.068 >10 >100.6  9 0.014 >10 >10 9.5 22 0.016 >10 >10 >10 20 0.026 >10 >10 >10 330.027 >10 >10 2.0 32 0.037 >10 >10 0.6 28 0.045 >10 >10 >10 140.064 >10 >10 6.2 (Example 11)  1 0.015 >10 7.0 2.0  2 0.018 >10 >10 0.610 0.026 >10 >10 4.0

[0263] It will be appreciated that the compounds of formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compounds in vivo.

[0264] As mentioned earlier, medicaments containing a compound offormula (I) are also an object of the present invention, as is a processfor the manufacture of such medicaments, which process comprisesbringing one or more compounds of formula (I) and, if desired, one ormore other therapeutically valuable substances into a galenicaladministration form.

[0265] The pharmaceutical compositions may be administered orally, forexample in the form of tablets, coated tablets, dragées, hard or softgelatine capsules, solutions, emulsions or suspensions. Administrationcan also be carried out rectally, for example using suppositories;locally or percutaneously, for example using ointments, creams, gels orsolutions; or parenterally, e.g. intravenously, intramuscularly,subcutaneously, intrathecally or transdermally, using for exampleinjectable solutions. Furthermore, administration can be carried outsublingually or as opthalmological preparations or as an aerosol, forexample in the form of a spray.

[0266] For the preparation of tablets, coated tablets, dragées or hardgelatine capsules the compounds of the present invention may be admixedwith pharmaceutically inert, inorganic or organic excipients. Examplesof suitable excipients for tablets, dragées or hard gelatine capsulesinclude lactose, maize starch or derivatives thereof, talc or stearicacid or salts thereof.

[0267] Suitable excipients for use with soft gelatine capsules includefor example vegetable oils, waxes, fats, semi-solid or liquid polyolsetc.; according to the nature of the active ingredients it may howeverbe the case that no excipient is needed at all for soft gelatinecapsules.

[0268] For the preparation of solutions and syrups, excipients which maybe used include for example water, polyols, saccharose, invert sugar andglucose.

[0269] For injectable solutions, excipients which may be used includefor example water, alcohols, polyols, glycerine, and vegetable oils.

[0270] For suppositories, and local or percutaneous application,excipients which may be used include for example natural or hardenedoils, waxes, fats and semi-solid or liquid polyols.

[0271] The pharmaceutical compositions may also contain preservingagents, solubilising agents, stabilising agents, wetting agents,emulsifiers, sweeteners, colorants, odorants, salts for the variation ofosmotic pressure, buffers, coating agents or antioxidants. As mentionedearlier, they may also contain other therapeutically valuable agents.

[0272] It is a prerequisite that all adjuvants used in the manufactureof the preparations are non-toxic.

[0273] Intravenous, intramuscular or oral administration is a preferredform of use. The dosages in which the compounds of formula (I) areadministered in effective amounts depend on the nature of the specificactive ingredient, the age and the requirements of the patient and themode of application. In general, daily dosages of about 1 mg-1000 mg,preferably 5 mg-500 mg, per day come into consideration.

[0274] The following Examples shall illustrate preferred embodiments ofthe present invention but are not intended to limit the scope of theinvention. Other compounds of formula (I) can be prepared according tothe general methods described above or in analogy to the examples.

EXAMPLE 1 Preparation of (R,S)-α-amino-3-bromophenylacetonitrile

[0275]

[0276] NH₄Cl (2.14 g, 40 mmol) and NaCN (1.96 g, 40 mmol) are dissolvedin 20 ml H₂O and 20 ml MeOH and cooled to 0° C. A solution of3-bromobenzaldehyde (4.68 ml, 40 mmol) in 15 ml CH₂Cl₂ and 15 MeOH isadded dropwise over 30 min. The mixture is allowed to warm to RT andstirred for 0.5 h. NH₃ solution (25% in H₂O) (6 ml, 80 mmol) is added.The mixture is stirred for 16 h at RT. The organic solvents areevaporated and H₂O is added (5 to 10 ml). The water layer is extractedwith CH₂Cl₂ (2×50 ml) and the latter is washed with H₂O (20 ml) andbrine (20 ml), dried over Na₂SO₄ and evaporated. The oily residue isdissolved in 75 ml ether. While stirring vigorously dropwise a 4 M HClsolution in dioxane is added. A solid precipitates and is filtered anddried. To recrystallize the solid is dissolved in as little MeOH aspossible (do not heat!). Now, while stirring, ether is added untilprecipitation has finished. The precipitate is filtered and dried invacuo.

[0277] Yield: 40% MS: 229 (MNH4+)

EXAMPLE 2 Preparation of Chiral amino Nitrites(S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester

[0278] 25% aqueous ammonia (63 mmol) is added to the mixed anhydride(prepared from 8 mmol (S)-BOC-phenyl glycine and 8 mmoliso-butylchloroformate) at −10° C. The mixture is stirred for 1 h atthis temperature, then over night at RT and concentrated. The residue isdissolved in 20 ml ethyl acetate, washed with saturated sodiumbicarbonate, 2N HCL, brine dried over sodium sulfate and evaporated.

[0279] Yield: 97%, MS: 251 (MH+)

[0280] (R)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester isprepared analogously to (S)-(Carbamoyl-phenyl-methyl)-carbamic acidtert-butyl ester

Preparation of (S)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester

[0281] (S)-(Carbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester(1.93 g, 7.7 mmol) and triethylamine (2.4 ml, 17 mmol) are dissolved inTHF (40 ml) and trifluoroacetic acid anhydride (1.2 ml, 8.5 mmol) isadded at 0° C. The mixture is stirred at 0° C. for 3 h and evaporated.Dichloromethane and water are added. The organic phase is separated,dried over sodium sulfate and evaporated. The crude product is purifiedby chromatography (silica gel, ethyl acetate/hexane=8:2, R_(f)=0.3).

[0282] Yield: 86%, MS: 250 (MH+18)

[0283] (R)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester isprepared analogously to (S)-(Cyano-phenyl-methyl)-carbamic acidtert-butyl ester

Preparation of (S)-Amino-phenyl-acetonitrile hydrochloride

[0284] (S)-(Cyano-phenyl-methyl)-carbamic acid tert-butyl ester (1.5 g,6.6 mmol) is dissolved in 30 ml ethyl acetate and 4N HCl in ethylacetate (33 ml) is added at 0° C. The mixture is stirred at RT for 3 hand evaporated. The product is washed with dietyl ether and dried invacuo, (silica gel, ethyl acetate, R_(f)=0.7).

[0285] Yield: 84%, MS: 151 (MH+18)

[0286] (R)-Amino-phenyl-acetonitrile hydrochloride is preparedanalogously to (S)-Amino-phenyl-acetonitrile hydrochloride.

EXAMPLE 3 Preparation of(1RS,2RS,5RS)-3-Aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester)

[0287]

[0288] Trans-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (0.50 g, 3.54mmol) is suspended in 15 ml MeOH (under argon) and cooled to 0° C.Thionylchloride (0.28 ml, 3.90 mmol) is added slowly over 10 min. Thereaction mixture is refluxed for 2.5 h. The solvent is evaporatedleaving an oily residue which is dissolved in CH₂Cl₂ (20 ml). Theorganic layer is washed with saturated Na₂CO₃ (10 ml) and the H₂O layeris extracted again with CH₂Cl₂ (3×20 ml). The collected organic layersare washed with brine (30 ml), dried over Na₂—SO₄ and evaporated,leaving a yellow oil.

[0289] Yield: 98%.

Preparation of trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylicacid methyl ester

[0290]

[0291] The (1RS, 2RS, 5RS)-3-Aza-bicyclo[3.1.0]hexane-2-carboxylic acidmethyl ester (0.55 g, 3.1 mmol) is dissolved in 20 ml CH₂Cl₂.Benzoylchloride (0.43 ml, 3.7 mmol) and N-methylmorpholine (NMM, 0.75ml, 6.8 mmol) are added. 4-Dimethylaminopyridine (DMAP, 38 mg, 0.31mmol) is added. The reaction mixture is stirred at RT for 16 h. Thesolvent is evaporated leaving an slightly yellow oil which is purifiedby column chromatography (silica, R_(f)=0.5, ethyl acetate/hexane 1:1).

[0292] Yield 52%, MS: 246 (MH+)

Preparation of trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylicacid

[0293]

[0294] Trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acidmethyl ester (0.392 g, 1.6 mmol) and 2 N NaOH (1.6 ml, 3.2 mmol) aredissolved in 20 ml MeOH. The mixture is stirred at RT for 6 h. Thesolution is concentrated, the residue is dissolved in ethyl acetate (30ml) and extracted with H₂O (2×15 ml). The collected H₂O layers areneutralized with 2 N HCl and extracted with ethyl acetate (2×20 ml). Thecollected ethyl acetate layers are washed with brine (30 ml), dried overNa₂SO₄ and evaporated leaving a white solid which is dried in vacuo.

[0295] Yield 90%.

EXAMPLE 4 Preparation oftrans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid[(3-bromo-phenyl)-cyano-methyl] -amide

[0296]

[0297] Trans-3-Benzoyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(0.201 g, 0.87 mmol), DL-α-amino-3-bromophenylacetonitrile (0.215 g,0.87 mmol), O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′ ,N′-tetramethyluroniumtetrafluoroborate (TPTU, 0.258 g, 0.87 mmol) and N-Ethyldiisopropylamine(0.45 ml, 2.61 mmol) are dissolved in 25 ml MeCN. The mixture is stirredat RT for 16 h. The solution is concentrated, the residue is dissolvedin ethyl acetate (30 ml) and extracted with H₂O (2×15 ml). The H₂Olayers are extracted with ethyl acetate (20 ml). The collected ethylacetate layers are washed with saturated NaHCO₃ (2×20 ml), brine (30ml), dried over Na₂SO₄ and evaporated. The yellow oil is purified bypreparative HPLC. column: HP-CombiHT XDB-C18, 21.2 mmI.D. × 50 mm,Series No DN 1020 method: Flow: 40 ml/min   0 min 80% water, 20%acetonitrile 0.2 min 80% water, 20% acetonitrile 3.5 min  5% water, 95%acetonitrile 4.7 min  5% water, 95% acetonitrile 4.8 min 80% water, 20%acetonitrile 4.9 min 80% water, 20% acetonitrile machine: Prep HPLCSystem Dynamax Model SD-1, UV-1 Yield 15%, MS: 441 (MNH4+)

EXAMPLE 5 Preparation of (S)-2-{(R)- and(S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester (Mixture of epimers, METHOD F)

[0298]

[0299] A solution of 0.7 mmol (S)-Pyrrolidine-1,2-dicarboxylic acid1-benzyl ester (educt 1), 5.2 mmol N-methylmorpholin, 0.15 mmol HOBT and1.78 mmol EDCI in 12 ml CH₂Cl₂ is added to 0.97 mmol(R,S)-Amino-(3-chloro-phenyl)-acetonitrile-hydrochloride (educt 2).After shaking overnight the reaction mixture is extracted with 10 ml 1NHCl and the CH₂Cl₂ was evaporated. The compound is purified by HPLC:column: HP-CombiHT XDB-C18, 21.2 mmI.D. × 50 mm, Series No DN 1020method: Flow: 40 ml/min   0 min 80% water, 20% acetonitrile 0.2 min 80%water, 20% acetonitrile 3.5 min  5% water, 95% acetonitrile 4.7 min  5%water, 95% acetonitrile 4.8 min 80% water, 20% acetonitrile 4.9 min 80%water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1,UV-1 Yield: 43%, MS: 396 (M-H)

EXAMPLE 6 Preparation of (S)-Pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-chloro-phenyl)-methyl] amide-trifluoroacetate (Mixture ofepimers, METHOD G)

[0300]

[0301] To a solution of 15.7 mmol (S)-Pyrrolidine-1,2-dicarboxylic acid1-tert.butyl ester, 17.2 mmol(R,S)-Amino-(3-chloro-phenyl)-acetonitrile-hydrochloride, 1.57 mmol HOBTand 18.8 mmol EDCI in 150 ml CH₂Cl₂ is added 109.7 mmolN-methylmorpholine. After stirring overnight at RT the reaction mixtureis extracted with 150 ml 10% KHSO₄ and 150 ml sat. NaHCO₃, dried overMgSO₄, evaporated and purified by flash chromatography (4 cm Glassfrit,2 cm silicagel 0.04-0.063, eluent 400 ml CH₂Cl₂). BOC-cleavage isperformed with 17 ml TFA in 50 ml CH₂Cl₂ within 4 hours at RT.Evaporation yields a brown oil which iss used without furtherpurification.

EXAMPLE 7 Preparation of (S)-1-(3-Cyclopentyl-propionyl)pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-chloro-phenyl)-cyano-methyl]-amide (Mixture of epimers, METHOD H)

[0302]

[0303] To a solution of 0.17 mmol 1:1mixture of Pyrrolidine-2-carboxylicacid (R)- and (S)-cyano-(3-chloro-phenyl)-methyl-amide-trifluoroacetate(educt 1) in 3 ml CH₂Cl₂ is added a solution of 0.187 mmol 3-Cyclopentylpropionylchloride (educt 2) in 1 ml CH₂Cl₂. To this mixture is added0.36 mmol triethylamine. After shaking overnight at RT formic acid isadded, the CH₂Cl₂ is evaporated and the compound purified by HPLC:column: HP-CombiHT XDB-C18, 21.2 mmI.D. × 50 mm, Series No DN 1020method: Flow: 40 ml/min   0 min 80% water, 20% acetonitrile 0.2 min 80%water, 20% acetonitrile 3.5 min  5% water, 95% acetonitrile 4.7 min  5%water, 95% acetonitrile 4.8 min 80% water, 20% acetonitrile 4.9 min 80%water, 20% acetonitrile machine: Prep HPLC System Dynamax Model SD-1,UV-1 Yield: 25%, MS: 388 (MH+)

EXAMPLE 8 Preparation of(S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide (Mixture of epimers,METHOD H)

[0304]

[0305] To a solution of 0.17 mmol 1:1 mixture ofPyrrolidine-2-carboxylic acid (R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide-trifluoroacetate(educt 1) in 3 ml CH₂Cl₂ is added a solution of 0.187 mmolNaphthalene-1-sulfonyl chloride (educt 2) in 1 ml CH₂Cl₂. To thismixture is added 0.36 mmol triethylamin. After shaking overnight at RTformic acid is added, the CH₂Cl₂ is evaporated and the compound purifiedby HPLC: column: HP-CombiHT XDB-C18, 21.2 mmI.D. × 50 mm, Series No DN1020 method: Flow: 40 ml/min   0 min 80% water, 20% acetonitrile 0.2 min80% water, 20% acetonitrile 3.5 min  5% water, 95% acetonitrile 4.7 min 5% water, 95% acetonitrile 4.8 min 80% water, 20% acetonitrile 4.9 min80% water, 20% acetonitrile machine: Prep HPLC System Dynamax ModelSD-1, UV-1 Yield:19%, MS: 497 (MNH4+)

EXAMPLE 9 Preparation of (S)-Pyrrolidine-1,2-dicarboxylic acid 2-{[(R)-and (S)-(3-chloro-phenyl)-cyano-methyl]-amide[1-(R)-(1-naphthalen-1-yl-ethyl)-amide] (Mixture of epimers,METHOD H)

[0306]

[0307] To a solution of 0.17 mmol 1:1 mixture ofPyrrolidine-2-carboxylic acid (R)- and(S)-cyano-(3-chloro-phenyl)-methyl-amide-trifluoroacetate (educt 1) in 3ml CH₂Cl₂ is added a solution of 0.187 mmol(R)-1-(1-Isocyanato-ethyl)-naphthalene (educt 2) in 1 ml CH₂Cl₂. To thismixture is added 0.36 mmol triethylamin. After shaking overnight at RTformic acid is added, the CH₂Cl₂ is evaporated and the compound purifiedby HPLC: column: HP-CombiHT XDB-C18, 21.2 mmI.D. × 50 mm, Series No DN1020 method: Flow: 40 ml/min   0 min 80% water, 20% acetonitrile 0.2 min80% water, 20% acetonitrile 3.5 min  5% water, 95% acetonitrile 4.7 min 5% water, 95% acetonitrile 4.8 min 80% water, 20% acetonitrile 4.9 min80% water, 20% acetonitrile machine: Prep HPLC System Dynamax ModelSD-1, UV-1 Yield:19%, MS: 461 (MH+)

[0308] EXAMPLE 10 Preparation of other compounds of formula (I) Severaladditional compounds of formula (I) have been prepared. The followingtable shows an overview of the products, the educts and the method usedfor the preparation. No. Compound Method Educt 1 Educt 2 MS 10.1(1RS,2RS,5SR)-2-{[(RS)-or-[(SR)-Cyano- E (1RS, 2RS, 5SR)-3-Aza-(R,S)-Amino-(3,4- 453 (MNH₄ ⁺)(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}- bicyclo [3.1.0]hexane-2,3-dimethoxy-phenyl)- 3-aza-bicyclo[3.1.0]hexane-3-carboxylic aciddicarboxylic acid 3-benzyl ester acetonitrile hydrochloride benzyl ester10.2 (S)-2-1(R)-(Cyano-phenyl-methyl)- E (S)-Pyrrolidine-1,2- (R)-Amino-phenyl- 422 (M-OAc) carbamoyl]-pyrrolidine-1-carboxylic aciddicarboxylic acid 1-benzyl ester acetonitrile hydrochloride benzyl ester10.3 (S)-2-[(S)-(Cyano-phenyl-methyl)- E (S)-Pyrrolidine-1,2-(S)-Amino-phenyl- 422 (M-OAc) carbamoyl]-pyrrolidine-1-carboxylic aciddicarboxylic acid 1-benzyl ester acetonitrile hydrochloride benzyl ester10.4 (S)-1-(3-methyl-butyryl)-pyrrolidine-2- E (S)-1-(3-Methyl-butyryl)-(R,S)-Amino-phenyl- 331 (MNH₄ ⁺) carboxylic acid(R)-and(S)-(cyano-phenyl- pyrrolidine-2-carboxylic acid acetonitrilehydrochloride methyl)-amide 10.5 (S)-2-{(S)-and(R)-[Cyano-(3-methoxy- E(S)-Pyrrolidine-1,2- (R,S)-Amino-(3-methoxy- 394 (MH⁺)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.6 (S)-2-{(S)-and(R)-[(3-Bromo-phenyl)- E (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-bromo- 459 (MNH₄ ⁺)cyano-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzyl esterphenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride 10.7(S)-2-{(S)-and(R)-[Cyano-(3-hydroxy- E (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-hydroxy- 378 (M-H)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.8 (S)-2-[(R)-and(S)-(Cyano-cyclopropyl- F (S)-Pyrrolidine-1,2-(R,S)-Amino-cyclopropyl- 350 (MNa⁺)methyl)-carbamoyl]-pyrrolidine-1-carboxylic dicarboxylic acid 1-benzylester acetonitrile hydrochloride acid benzyl ester 10.9(S)-2-[(R)-and(S)-(Benzo[1,3]dioxol-5-yl- F (S)-Pyrrolidine-1,2-(R,S)-Amino- 425 (MNH₄ ⁺) cyano-methyl)-carbamoyl]-pyrrolidine-1-dicarboxylic acid 1-benzyl ester benzo[1,3]dioxol-5-yl- carboxylicacidbenzyl ester acetonitrile hydrochloride 10.10(R)-4-{(R)-and(S)-[Cyano-(3,4-dimethoxy- F (R)-Thiazolidine-3,4-(R,S)-Amino-(3,4- 464 (MNa⁺) phenyl)-methyl]-carbamoyl}-thiazolidine-3-dicarboxylic acid 3-benzyl ester dimethoxy-phenyl)- carboxylic acidbenzyl ester acetonitrile hydrochloride 10.11(2S,3R)-2-{(R)-and(S)-[Cyano-(3,4- F (2S,3R)-3-Methyl-pyrrolidine-(R,S)-Amino-(3,4- 438 (MH⁺) dimethoxy-phenyl)-methyl]-carbamoyl}-3-1,2-dicarboxylic acid 1-benzyl dimethoxy-phenyl)-methyl-pyrrolidine-1-carboxylic acid benzyl ester acetonitrilehydrochloride ester 10.12 (S)-1-Benzylthiocarbamoyl-pyrrolidine-2- HPyrrolidine-2-carboxylic acid Benzylisothiocyanate 423 (MH⁺) carboxylicacid((R)-and(S)- ((R)-and(S)- benzo[1,3]dioxol-5-yl-cyano-methyl)-amidebenzo[1,3]dioxol-5-yl-cyano- methyl)-amide; compound withtrifluoro-acetic acid 10.13 (S)-1-Benzylthiocarbamoyl-pyrrolidine-2- HPyrrolidine-2-carboxylic acid Benzylisothiocyanate 439 (MH⁺) carboxylicacid [(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.14(S)-1-[(Furan-2-ylmethyl)-thiocarbamoyl]- H Pyrrolidine-2-carboxylicacid 2-Isothiocyanatomethyl- 429 (MH⁺) pyrrolidine-2-carboxylic acid[(R)-and(S)- [(R)-and(S)-cyano-(3,4- furan cyano-(3,4-dimethoxy-phenyl)-methyl]- dimethoxy-phenyl)-methyl]- amide amide;compound with trifluoro-acetic acid 10.15(S)-1-Benzylthiocarbamoyl-pyrrolidine-2- H Pyrrolidine-2-carboxylic acidBenzylisothiocyanate 412 (MH⁺) carboxylic acid [(R)-and(S)-(3-chloro-[(R)-and(S)-(3-chloro- phenyl)-cyano-methyl]-amidephenyl)-cyano-methyl]-amide; compound with trifluoro- acetic acid 10.16(S)-1-(3-Fluoro-benzylthiocarbamoyl)- H Pyrrolidine-2-carboxylic acid3-Fluoro 431 (MH⁺) pyrrolidine-2-carboxylic acid [(R)-and(S)-[(R)-and(S)-(3-chloro- benzylisothiocyanate(3-chloro-phenyl)-cyano-methyl]-amide phenyl)-cyano-methyl]-amide;compound with trifluoro- acetic acid 10.17(S)-2-((R)-and(S)-1-Cyano-3-phenyl- F (S)-Pyrrolidine-1,2-(R,S)-2-Amino-4-phenyl- 392 (MH⁺)propylcarbamoyl)-pyrrolidine-1-carboxylic dicarboxylic acid 1-benzylester butyronitrile hydrochloride acid benzyl ester 10.18(R)-4-{(R)-and(S)-[(4-Chloro-phenyl)- F (R)-Thiazolidine-3,4-(R,S)-Amino-(4-chloro- 416 (MH⁺)cyano-methyl]-carbamoyl}-thiazolidine-3- dicarboxylic acid 3-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.19 (S)-2-{(R)-and(S)-[(3-Chloro-phenyl)- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-chloro- 396 (MH⁺) cyano-methyl]-carbamoyl}-pyrrolidine-1-dicarboxylic acid 1-benzyl ester phenyl)-acetonitrile carboxylic acidbenzyl ester hydrochloride 10.20(S)-2-[(R)-and(S)-(Cyano-o-tolyl-methyl)- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(2-methyl- 378 (MH⁺) carbamoyl]-pyrrolidine-1-carboxylicacid dicarboxylic acid 1-benzyl ester phenyl)-acetonitrile benzyl esterhydrochloride 10.21 (S)-2-{(R)-and(S)-[Cyano-(2,4-dimethoxy- F(S)-Pyrrolidine-1,2- (R,S)-Amino-(2,4- 422 (M-H)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester dimethoxy-phenyl)- carboxylic acid benzyl ester acetonitrilehydrochloride 10.22 (S)-2-{(R)-and(S)-[(3-Bromo-phenyl)- F(S)-Pyrrolidine-1,2- (R,S)-Amino-(3-bromo- 442 (M-H)cyano-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzyl esterphenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride 10.23(S)-2-{(R)-and(S)-[Cyano-(3-fluoro- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-fluoro- 380 (M-H)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.24 (S)-2-[(R)-and(S)-(Cyano-m-tolyl-methyl)- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-methyl- 376 (M-H) carbamoyl]-pyrrolidine-1-carboxylicacid dicarboxylic acid 1-benzyl ester phenyl)-acetonitrile benzyl esterhydrochloride 10.25 (S)-2-{(R)-and(S)-[(4-Bromo-phenyl)- F(S)-Pyrrolidine-1,2- (R,S)-Amino-(4-bromo- 442 (M-H)cyano-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzyl esterphenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride 10.26(S)-2-{(R)-and(S)-[Cyano-(3,4,5- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(3,4,5- 452 (M-H) trimethoxy-phenyl)-methyl]-carbamoyl}-dicarboxylic acid 1-benzyl ester trimethoxy-phenyl)-pyrrolidine-1-carboxylic acid benzyl ester acetonitrile hydrochloride10.27 (S)-2-{(R)-and(S)-[Cyano-(3-phenoxy- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(3-phenoxy- 454 (M-H)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.28 (S)-2-{(R)-and(S)-[4-Benzyloxy-3- F (S)-Pyrrolidine-1,2-(R,S)-Amino-(4-benzyloxy- 498 (M-H)methoxy-phenyl)-cyano-methyl]-carbamoyl}- dicarboxylic acid 1-benzylester 3-methoxy-phenyl)- pyrrolidine-1-carboxylic acid benzyl esteracetonitrile hydrochloride 10.30(S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Napthalene-2-sulfonyl 480 (MH⁺) 2-carboxylic acid[(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4- chloridedimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.31(S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Naphalene-1-sulfonyl 481 (MH⁺) 2-carboxylic acid((R)-and(S)-((R)-and(S)- chloride benzo[1,3]dioxol-5-yl-cyano-methyl)-amidebenzo[1,3]dioxol-5-yl-cyano- methyl)-amide; compound withtrifluoro-acetic acid 10.32 (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-H Pyrrolidine-2-carboxylic acid Cyclopentyl-propionyl 398 (MH⁺)2-carboxylic acid((R)-and(S)- ((R)-and(S)- chloridebenzo[1,3]dioxol-5-yl-cyano-methyl)-amide benzo[1,3]dioxol-5-yl-cyano-methyl)-amide; compound with trifluoro-acetic acid 10.33(S)-1-Benzyloxyacetyl-pyrrolidine-2- H Pyrrolidine-2-carboxylic acidBenzyloxy-acetyl chloride 422 (MH⁺) carboxylic acid((R)-and(S)-((R)-and(S)- benzo[1,3]dioxol-5-yl-cyano-methyl)-amidebenzo[1,3]dioxol-5-yl-cyano- methyl)-amide; compound withtrifluoro-acetic acid 10.34 (S)-1-(5-Dimethylamino-naphthalene-1- HPyrrolidine-2-carboxylic acid 5-Dimethylamino- 523 (MH⁺)sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- [(R)-and(S)-cyano-(3,4-naphthalene-1-sulfonyl and(S)-cyano-(3,4-dimethoxy-phenyl)-dimethoxy-phenyl)-methyl]- chloride methyl]-amide amide; compound withtrifluoro-acetic acid 10.35 (S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-H Pyrrolidine-2-carboxylic acid Naphthalene-1-sulfonyl 497 (MNH₄ ⁺)2-carboxylic acid [(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4-chloride dimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]-amide; compound with trifluoro-acetic acid 10.36(S)-1-(Naphthalene-2-carbonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Naphthalene-2-carbonyl 444 (MH⁺) 2-carboxylic acid[((R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4- chloridedimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.37(S)-1-(Naphthalene-1-carbonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Naphthalene-1-carbonyl 444 (MH⁺) 2-carboxylic acid[(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4- chloridedimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.38(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Cyclopentyl-propionyl 414 (MH⁺) 2-carboxylic acid[(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4- chloridedimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.39(S)-1-Benzyloxyacetyl-pyrrolidine-2- H Pyrrolidine-2-carboxylic acidBenzyloxyacetyl chloride 438 (MH⁺) carboxylic acid[(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]- amide;compound with trifluoro-acetic acid 10.40(S)-1-(Naphthalene-1-carbonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Naphthalene-1-carbonyl 418 (MH⁺) 2-carboxylic acid[(R)-and(S)-(3-chloro- [(R)-and(S)-(3-chloro- chloridephenyl)-cyano-methyl]-amide phenyl)-cyano-methyl]-amide; compound withtrifluoro- acetic acid 10.41(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Cyclopentyl-propionyl 388 (MH⁺) 2-carboxylic acid[(R)-and(S)-(3-chloro- [(R)-and(S)-(3-chloro- chloridephenyl)-cyano-methyl]-amide phenyl)-cyano-methyl]-amide; compound withtrifluoro- acetic acid 10.42 (S)-1-Phenylacetyl-pyrrolidine-2-carboxylicH Pyrrolidine-2-carboxylic acid Phenylacetyl chloride 382 (MH⁺) acid[(R)-and(S)-(3-chloro-phenyl)-cyano- [(R)-and(S)-(3-chloro-methyl]-amide phenyl)-cyano-methyl]-amide; compound with trifluoro-acetic acid 10.43 (S)-1-Benzyloxyacetyl-pyrrolidine-2- HPyrrolidine-2-carboxylic acid Benzyloxyacetyl chloride 412 (MH⁺)carboxylic acid [(R)-and(S)-(3-chloro- [(R)-and(S)-(3-chloro-phenyl)-cyano-methyl]-amide phenyl)-cyano-methyl}-amide; compound withtrifluoro- acetic acid 10.44 (S)-Pyrrolidine-1,2-dicarboxylic acid2-{[(R)- H Pyrrolidine-2-carboxylic acid (R)-1-(1-Isocyanato-ethyl)- 461(MH⁺) and(S)-(3-chloro-phenyl)-cyano-methyl]- [(R)-and(S)-(3-chloro-naphthalene amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-phenyl)-cyano-methyl]-amide; amide] compound with trifluoro- acetic acid10.45 (S)-1-(Naphthalene-1-carbonyl)-pyrrolidine- H(S)-Pyrrolidine-2-carboxylic Napthalene-1-carbonyl 462 (MH⁺)2-carboxylic acid [(R)-and(S)-(3-bromo- acid [(R)-and(S)-3-bromo-chloride phenyl)-cyano-methyl]-amide phenyl)-cyano-methyl]-amide;compound with trifluoro- acetic acid 10.46(S)-1-Phenylacetyl-pyrrolidine-2-carboxylic H(S)-Pyrrolidine-2-carboxylic Phenylacetyl chloride 426 (MH⁺) acid[(R)-and(S)-(3-bromo-phenyl)-cyano- acid [(R)-and(S)-3-bromo-methyl]-amide phenyl)-cyano-methyl]-amide; compound with trifluoro-acetic acid 10.47 (S)-1-Benzyloxyacetyl-pyrrolidine-2- H(S)-Pyrrolidine-2-carboxylic Benzyloxyacetyl chloride 456 (MH⁺)carboxylic acid [(R)-and(S)-(3-bromo- acid [(R)-and(S)-3-bromo-phenyl)-cyano-methyl]-amide phenyl)-cyano-methyl]-amide; compound withtrifluoro- acetic acid 10.48 (S)-Pyrrolidine-1,2-dicarboxylic acid2-{[(R)- H (S)-Pyrrolidine-2-carboxylic (R)-1-(1-Isocyanato-ethyl)- 507(MH⁺) and(S)-(3-bromo-phenyl)-cyano-methyl]- acid [(R)-and(S)-3-bromo-naphthalene amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-phenyl)-cyano-methyl]-amide; amide] compound with trifluoro- acetic acid10.49 (S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine- HPyrrolidine-2-carboxylic acid Cyclopentyl-propionyl 384 (MH⁺)2-carboxylic acid [(R)-and(S)-cyano-(3- [(R)-and(S)-cyano-(3- chloridemethoxy-phenyl)-methyl]-amide methoxy-phenyl)-methyl]- amide; compoundwith trifluoro-acetic acid 10.50(S)-1-Phenylacetyl-pyrrolidine-2-carboxylic H Pyrrolidine-2-carboxylicacid Phenylacetyl chloride 378 (MH⁺) acid [(R)-and(S)-cyano-(3-methoxy-[(R)-and(S)-cyano-(3- phenyl)-methyl]-amide methoxy-phenyl)-methyl]-amide; compound with trifluoro-acetic acid 10.51(S)-1-Benzyloxyacetyl-pyrrolidine-2- H Pyrrolidine-2-carboxylic acidBenzyloxyacetyl chloride 408 (MH⁺) carboxylic acid [(R)-and(S)-cyano-(3-[(R)-and(S)-cyano-(3- methoxy-phenyl)-methyl]-amidemethoxy-phenyl)-methyl]- amide; compound with trifluoro-acetic acid10.52 2-((R)-and(S)-1-Cyano-3-phenyl- F (S)-Pyrrolidine-1,2-(R,S)-2-Amino-4-phenyl- 392 (MH⁺)propylcarbamoyl)-pyrrolidine-1-carboxylic dicarboxylic acid 1-benzylester butyronitrile hydrochloride acid benzyl ester 10.53(S)-2-{[(R)-and(S)-Cyano-(3-methoxy- F (S)-Pyrrolidine-1,2-(R,S)-2-Amino-(3-methoxy- 394 (MH⁺)phenyl)-methyl]-carbamoyl}-pyrrolidine-1- dicarboxylic acid 1-benzylester phenyl)-acetonitrile carboxylic acid benzyl ester hydrochloride10.54 (S)-2-{(R)-and(S)-[Cyano-(3,4-dimethoxy- F (S)-Pyrrolidine-1,2-(R,S)-2-Amino-(3,4- 441 (MH⁺) phenyl)-methyl]-carbamoyl}-pyrrolidine-1-dicarboxylic acid 1-benzyl ester dimethoxy-phenyl)- carboxylic acidbenzyl ester acetonitrile hydrochloride 10.55(S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine- H Pyrrolidine-2-carboxylicacid Phenyl-ethenesulfonyl 440 (MH⁺) 2-carboxylic acid((R)-and(S)-((R)-and(S)- chloride benzo[1,3]dioxol-5-yl-cyano-methyl)-amidebenzo[1,3]dioxol-5-yl-cyano- methyl)-amide; compound withtrifluoro-acetic acid 10.56 (S)-Pyrrolidine-1,2-dicarboxylic acid2-{(R)- H Pyrrolidine-2-carboxylic acid (S)-1-(1-Isocyanato-ethyl)- 487(MH⁺) and(S)-[cyano-(3,4-dimethoxy-phenyl) [(R)-and(S)-cyano-(3,4-naphthalene methyl]-amide}1-[(S)-(1-naphthalen-1-yl-dimethoxy-phenyl)-methyl]- ethyl)-amide] amide; compound withtrifluoro-acetic acid 10.57 (S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine-H Pyrrolidine-2-carboxylic acid Phenyl-ethenesulfonyl 456 (MH⁺)2-carboxylic acid [(R)-and(S)-cyano-(3,4- [(R)-and(S)-cyano-(3,4-chloride dimethoxy-phenyl)-methyl]-amide dimethoxy-phenyl)-methyl]-amide; compound with trifluoro-acetic acid

[0309] The following methods were used:

METHOD E Coupling of Protected Amino Acids with Amino Nitrites

[0310] The protected amino acid, the amino nitrile, TPTU(O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,N′ ,N′-tetramethyluroniumtetrafluoroborate) and Hünigsbase (N-Ethyldiisopropylamine) aredissolved in MeCN. The mixture is stirred at RT for 6-16 h. The solutionis concentrated and the residue is dissolved in ethyl acetate andextracted with H₂O. The H₂O layers are extracted with ethyl acetate. Thecombined ethyl acetate layers are washed NaHCO₃, brine, dried overNa₂SO₄ and evaporated. The crude product is purified by columnchromatography.

[0311] Yield 60-90%.

METHOD F Z-AS+Amino Nitrile

[0312] A solution of leq (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzylester, 7 eq N-methylmorpholin, 0.2 eq HOBT and 2.4 eq EDCI in 7 mlCH₂Cl₂ is added to 1.1-1.3 eq amino nitrile-HCl. After shaking overnightthe reaction mixture is extracted with 1N HCl and the CH₂Cl₂ isevaporated. The compounds are purified by HPLC: column: HP-CombiHTXDB-C18, 21.2 mm I.D. × 50 mm, Series No DN 1020 method: Flow: 40 ml/min  0 min 80% water, 20% acetonitrile 0.2 min 80% water, 20% acetonitrile3.5 min  5% water, 95% acetonitrile 4.7 min  5% water, 95% acetonitrile4.8 min 80% water, 20% acetonitrile 4.9 min 80% water, 20% acetonitrilemachine: Prep HPLC System Dynamax Model SD-1, UV-1

METHOD H Amino Acid Nitrile (Educt 1)+(Educt 2)

[0313] Crude 1:1 mixture of Pyrrolidine-2-carboxylic-amide-trifluoroacetate (educt 1)+a.

[0314] Carbonylchloride (educt 2) or b. sulfonylchloride (educt 2) or c.Isothiocyanate (educt 2)+ triethylamine

[0315] To a solution of leq Pyrrolidine-2-carboxylic acid amide-TFA(educt 1) in CH₂Cl₂ is added a solution of 1.1 eq carbonylchloride(educt 2) or sulfonylchloride (educt 2) or isothiocyanate (educt 2) inCH₂Cl₂. To this mixture is added 2.1 eq triethylamine. After shakingovernight at RT formic acid is added, CH₂Cl₂ is evaporated and thecompound purified by HPLC: column: HP-CombiHT XDB-C18, 21.2 mm I.D. × 50mm, Series No DN 1020 method: Flow: 40 ml/min   0 min 80% water, 20%acetonitrile 0.2 min 80% water, 20% acetonitrile 3.5 min  5% water, 95%acetonitrile 4.7 min  5% water, 95% acetonitrile 4.8 min 80% water, 20%acetonitrile 4.9 min 80% water, 20% acetonitrile machine: Prep HPLCSystem Dynamax Model SD-1, UV-1

[0316] Preparation of other compounds of formula (I) The followingcompounds of formula (I) have been prepared from the correspondingeducts in analogy to example 10, method H. No. Compound Educt 1 Educt 2MS 11.1 (S)-1-[2-(3- Pyrrolidine-2- 3-Bromo- 471 (MH⁺) Bromo-phenyl)-carboxylic acid phenyl- ethanoyl]- ((R)- and (S)- acetyl pyrrolidine-2-benzo[1,3]dioxol- chloride carboxylic 5-yl-cyano-methyl)- acid (1-amide; compound benzo[1,3]dioxol- with trifluoro-acetic 5-yl-1-cyano-acid methyl)-amide 11.2 (S)-1-[2-(3- Pyrrolidine-2- 3-Bromo- 487 (MH⁺)Bromo-phenyl)- carboxylic acid phenyl- ethanoyl]- [(R)- and (S)- acetylpyrrolidine-2- cyano-(3,4-dime- chloride carboxylic thoxy-phenyl)- acid[1- methy]-amide; cyano-1-(3,4- compound with dimethyoxy-trifluoro-acetic phenyl)-methyl]- acid amide 11.3 (S)-1-[2-(4-Pyrrolidine-2- 4-Bromo- 487 (MH⁺) Bromo-phenyl)- carboxylic acid phenyl-ethanoyl]- [(R)- and (S)- acetyl pyrrolidine-2- cyano-(3,4-dime-chloride carboxylic thoxy-phenyl)- acid [1- methyl]-amide; cyano-1-(3,4-compound with dimethyoxy- trifluoro-acetic phenyl)-methyl]- acid amide11.4 (S)-1-[2-(4- Pyrrolidine-2- 4-Chloro- 417 (MH⁺) Chloro-phenyl)-carboxylic acid phenyl- ethanoyl]- [(R)- and (S)- acetyl pyrrolidine-2-(3-chloro-phenyl)- chloride carboxylic cyano-methyl]- acid [1-(3- amide;compound chloro-phenyl)- with trifluoro-acetic 1-cyano-methyl]- acidamide 11.5 (S)-1-[2-(4- Pyrrolidine-2- 4-Fluoro- 410 (MH⁺)Chloro-phenyl)- carboxylic acid phenyl- ethanoyl]- ((R)- and (S)- acetylpyrrolidine-2- benzo[1,3]dioxol- chloride carboxylic 5-yl-cyano-methyl)-acid [1-(3- amide; compound chloro-phenyl)- with trifluoro-acetic1-cyano-methyl]- acid amide 11.6 (S)-1-[2-(4- Pyrrolidine-2- 4-Chloro-442 (MH⁺) Chloro-phenyl)- carboxylic acid phenyl- ethanoyl]- [(R)- and(S)- acetyl pyrrolidine-2- cyano-(3,4-dime- chloride carboxylicthoxy-phenyl)- acid [1-cyano- methyl]-amide; 1-(3,4-dimethoxy- compoundwith phenyl)-methyl]- trifluoro-acetic amide acid 11.7 (S)-1-(2-o-Pyrrolidine-2- (2-Methyl- 438 (MH⁺) Tolyloxy- carboxylic acid phenoxy)-ethanoyl)- [(R)- and (S)- acetyl pyrrolidine-2- cyano-(3,4-dime-chloride carboxylic acid thoxy-phenyl)- [1-cyano-1-(3,4- methyl]-amide;dimethoxy- compound with phenyl)-methyl]- trifluoro-acetic amide acid11.8 (S)-1-(2-o- Pyrrolidine-2- (2-Methyl- 422 (MH⁺) Tolyloxy-carboxylic acid phenoxy)- ethanoyl)- ((R)- and (S)- acetylpyrrolidine-2- benzo[1,3]dioxol- chloride carboxylic acid5-yl-cyano-methyl)- (1-benzo[1,3]- amide; compound dioxol-5-yl-1- withtrifluoro-acetic cyano-methyl)- acid amide 11.9 (S)-1-[2- Pyrrolidine-2-4-Fluoro- 426 (MH⁺) (4-Fluoro- carboxylic acid phenyl- phenyl)- [(R)-and (S)- acetyl ethanoyl]- cyano-(3,4- chloride pyrrolidine-2-dimethoxy- carboxylic acid phenyl)-methyl]- [1-cyano-1- amide; compound(3,4-dimethoxy- with trifluoro- phenyl)-methyl]- acetic acid amide 11.10(S)-1-[2- Pyrrolidine-2- 4-Bromo- 471 (MH⁺) (4-Bromo- carboxylic acidphenyl- phenyl)- ((R)- and (S)- acetyl ethanoyl]- benzo[1,3]- chloridepyrrolidine-2- dioxol-5-yl- carboxylic acid cyano-methyl)-(1-benzo[1,3]- amide; compound dioxol-5-yl-1- with trifluoro-cyano-methyl)- acetic acid amide 11.11 (S)-1-[2- Pyrrolidine-2- 4-Bromo-461 (MH⁺) (4-Bromo- carboxylic acid phenyl- phenyl)- [(R)- and (S)-acetyl ethanoyl]- (3-chloro-phenyl)- chloride pyrrolidine-2-cyano-methyl]- carboxylic acid amide; compound [1-(3-chloro- withtrifluoro- phenyl)-1- acetic acid cyano-methyl]- amide 11.12 (S)-1-[2-Pyrrolidine-2- 4-Iodo- 518 (MH⁺) (4-Iodo- carboxylic acid phenyl-phenyl)- ((R)- and (S)- acetyl ethanoyl]- benzo[1,3]- chloridepyrrolidine-2- dioxol-5-yl- carboxylic acid cyano-methyl)-(1-benzo[1,3]- amide; compound dioxol-5-yl-1- with trifluoro-cyano-methyl)- acetic acid amide 11.13 (S)-1-[2- Pyrrolidine-2-4-Fluoro- 400 (MH⁺) (4-Fluoro- carboxylic acid phenyl- phenyl)- [(R)-and (S)- acetyl ethanoyl]- (3-chloro-phenyl)- chloride pyrrolidine-2-cyano-methyl]- carboxylic acid amide; compound [1-(3- with trifluoro-chloro-phenyl)- acetic acid 1-cyano-methyl]- amide 11.14 (S)-1-(4-Pyrrolidine-2- Phenyl- 436 (MH⁺) Phenyl- carboxylic acid butyric-butanoyl)- [(R)- and (S)- chloride pyrrolidine- cyano-(3,4-dime-2-carboxylic thoxy-phenyl)- acid methyl]-amide; [1-cyano-1- compoundwith (3,4-dimethoxy- trifluoro-acetic acid phenyl)-methyl]- amide 11.15(S)-1-[2- Pyrrolidine-2- 3-Bromo- 461 (MH⁺) (3-Bromo- carboxylic acidphenyl- phenyl)- [(R)- and (S)- acetyl ethanoyl]- (3-chloro-phenyl)-chloride pyrrolidine-2- cyano-methyl]- carboxylic acid amide;[1-(3-chloro- compound with phenyl)-1-cyano- trifluoro-acetic acidmethyl]- amide 11.16 (S)-1-(2- Pyrrolidine-2- 3,4-(Meth- 426 (MH⁺)Benzo[1,3]- carboxylic acid ylendioxy) dioxol-5-yl- [(R)- and (S)-phenyl- ethanoyl)- (3-chloro-phenyl)- acetyl pyrrolidine-2-cyano-methyl]- chloride carboxylic acid amide; [1-(3-chloro- compoundwith phenyl)-1-cyano- trifluoro-acetic acid methyl]- amide 11.17(S)-1-(2- Pyrrolidine-2- Phenoxy- 424 (MH⁺) Phenoxy- carboxylic acidacetyl ethanoyl)- [(R)- and (S)- chloride pyrrolidine-2- cyano-(3,4-carboxylic acid dimethoxy-phenyl)- [1-cyano- methyl]- 1-(3,4-dimethoxy-amide; compound phenyl)-methyl]- with trifluoro-acetic amide acid 11.18(S)-1-(2-o- Pyrrolidine-2- (2-Methyl- 412 (MH⁺) Tolyloxy- carboxylicacid phenoxy)- ethanoyl)- [(R)- and (S)- acetyl pyrrolidine-2-(3-chloro-phenyl)- chloride carboxylic acid cyano-methyl]- [1-(3- amide;chloro-phenyl)-1- compound cyano-methyl]- with trifluoro- amide aceticacid 11.19 (S)-1-(2- Pyrrolidine-2- 3,4- 436 (MH⁺) Benzo[1,3]-carboxylic acid (Methyl- dioxol-5-yl- ((R)- and (S)- endioxy)-ethanoyl)- benzo[1,3]- phenyl- pyrrolidine-2- dioxol-5-yl- acetylcarboxylic acid cyano-methyl)- chloride (1-benzo[1,3]- amide; compounddioxol-5-yl-1- with trifluoro-acetic cyano-methyl)- acid amide 11.20(S)-1-(2- Pyrrolidine-2- Phenoxy- 398 (MH⁺) Phenoxy- carboxylic acidacetyl ethanoyl)- [(R)- and (S)- chloride pyrrolidine-(3-chloro-phenyl)- 2-carboxylic acid cyano-methyl]- [1-(3-chloro- amide;compound phenyl)-1-cyano- with methyl]- trifluoro-acetic amide acid11.21 (S)-1-(2- Pyrrolidine-2- Phenyl- 382 (MH⁺) Phenyl- carboxylic acidacetyl ethanoyl)- [(R)- and (S)- chloride pyrrolidine-(3-chloro-phenyl)- 2-carboxylic acid cyano-methyl]- [1-(3-chloro- amide;compound phenyl)-1-cyano- with methyl]- trifluoro-acetic amide acid11.22 (S)-1-[2- Pyrrolidine-2- (4-Fluoro- 442 (MH⁺) (4-Fluoro-carboxylic acid phenoxy)- phenoxy)- [(R)- and (S)- acetyl ethanoyl]-cyano-(3,4- chloride pyrrolidine-2- dimethoxy- carboxylic acid phenyl)-[1-cyano-1-(3,4- methyl]- dimethoxy- amide; compound phenyl)- withtrifluoro- methyl]-amide acetic acid 11.23 (S)-1-(2- Pyrrolidine-2-3,4-(Meth- 452 (MH⁺) Benzo- carboxylic acid ylendioxy) [1,3]- [(R)- and(S)- phenyl- dioxol-5-yl- cyano-(3,4- acetyl ethanoyl)- dimethoxy-chloride pyrrolidine-2- phenyl)- carboxylic acid methyl]- [1-cyano-1-amide; compound (3,4-dimethoxy- with trifluoro- phenyl)-methyl]- aceticacid amide 11.24 (S)-1-(3- Pyrrolidine-2- Phenyl- 422 (MH⁺) Phenyl-carboxylic acid propionyl propanoyl)- [(R)- and (S)- chloridepyrrolidine- cyano-(3,4- 2-carboxylic acid dimethoxy- [1-cyano-1-phenyl)- (3,4-dimethoxy- methyl]- phenyl)-methyl]- amide; compound amidewith trifluoro- acid 11.25 (S)-1-[4- Pyrrolidine-2- (3,4-Meth- 480 (MH⁺)3,4-Dimethoxy- carboxylic acid oxy- phenyl)- ((R)- and (S)- phenyl)butanoyl]- benzo[1,3]- butyryl pyrrolidine-2- dioxol-5-yl- chloridecarboxylic acid cyano-methyl)- (1-benzo[1,3]- amide; dioxol-5-yl-1-compound cyano-methyl)- with trifluoro- amide acide 11.26 (S)-1-[4-Pyrrolidine-2- (3,4-Meth- 470 (MH⁺) (3,4-Dimethoxy- carboxylic acid oxy-phenyl)- [(R)- and (S)- phenyl) butanoyl]- (3-chloro-phenyl)- butyrylpyrrolidine-2- cyano-methyl]- chloride carboxylic acid amide;[1-(3-chloro- compound with phenyl)-1-cyano- trifluoro-aceticmethyl]-amide acid 11.27 (S)-1-[2- Pyrrolidine-2- 4-Iodo- 534 (MH⁺)(4-Iodo-phenyl)- carboxylic acid phenyl- ethanoyl]- [(R)- and (S)-acetyl pyrrolidine-2- cyano-(3,4- chloride carboxylic dimethoxy-phenyl)-acid methyl]-amide; [1-cyano- compound with 1-(3,4-dimethoxy-trifluoro-acetic phenyl)-methyl]- acid amide 11.28 (S)-1-[4-Pyrrolidine-2- (3,4-Meth- 496 (MH⁺) (3,4-Dimethoxy- carboxylic acid oxy-phenyl)-buta - [(R)- and (S)- phenyl) noyl]-pyrrolidine- cyano-(3,4-butyryl 2-carboxylic dimethoxy-phenyl)- chloride acid methyl]-amide;[1-cyano- compound with 1-(3,4-dimethoxy- trifluoro-aceticphenyl)-methyl]- acid amide 11.29 (S)-1-(3-1H- Pyrrolidine-2- 3-Indo-461 (MH⁺) Indol-3-yl- carboxylic acid leprop- propanoyl)- [(R)- and (S)-ionic pyrrolidine-2- cyano-(3,4- acid carboxylic dimethoxy-phenyl)-chloride acid methyl]-amide; [1-cyano- compound with 1-(3,4-dimethoxy-trifluoro-acetic phenyl)-methyl]- acid amide 11.30 (S)-1-(4-Phenyl-Pyrrolidine-2- Phenyl- 420 (MH⁺) butanoyl)- carboxylic acid butyrylpyrrolidine-2- ((R)- and (S)- chloride carboxylic acid benzo[1,3]-(1-benzo[1,3]- dioxol-5-yl-cyano- dioxol-5-yl-1- methyl)-amide;cyano-methyl)- compound with amide trifluoro-acetic acid 11.31(S)-1-(2-Phenyl- Pyrrolidine-2- (Phenyl- 414 (MH⁺) sulfanyl- carboxylicacid thio)- ethanoyl)- [(R)- and (S)- acetyl pyrrolidine-2-(3-chloro-phenyl)- chloride carboxylic acid cyano-methyl]- [1-(3-chloro-amide; phenyl)-1-cyano- compound with methyl]-amide trifluoro-aceticacid 11.32 (S)-1-(4-Cyclo- Pyrrolidine-2- Cyclo- 442 (MH⁺)hexyl-butanoyl)- carboxylic acid hexane- pyrrolidine-2- [(R)- and (S)-butyric carboxylic acid cyano-(3,4-dime- acid [1-cyano-1(3,4-thoxy-phenyl)- chloride dimethoxy- methyl]-amide; phenyl)-methyl]-compound with amide trifluoro-acetic acid 11.33 (S)-1-(3-Cyclo-Pyrrolidine-2- Cyclo- 412 (MH⁺) hexyl-propanoyl)- carboxylic acidhexane- pyrrolidine-2- ((R)- and (S)- propionic carboxylic acidbenzo[1,3]- acid (1-benzo[1,3]- dioxol-5-yl-cyano- chloridedioxol-5-yl-1- methyl)-amide; cyano-methyl)- compound with amidetrifluoro-acetic acid 11.34 (S)-1-[4-(4- Pyrrolidine-2- (4-Nitro- 481(MH⁺) Nitro-phenyl)- carboxylic acid benzene)- butanoyl]- [(R)- and (S)-butyryl pyrrolidine-2- cyano-(3,4- chloride carboxylic aciddimethoxy-phenyl)- [1-cyano-1-(3,4- methyl]-amide; dimethoxy- compoundwith phenyl)-methyl]- trifluoro-acetic amide acid 11.35 (S)-1-[2-(4-Pyrrolidine-2- (4-Iodo- 508 (MH⁺) Iodo-phenyl)- carboxylic acid phenyl-ethanoyl]- [(R)- and (S)- acetyl pyrrolidine-2- (3-chloro-phenyl)-chloride carboxylic acid cyano-methyl]- [1-(3-chloro- amide;phenyl)-1-cyano- compound with methyl]-amide trifluoro-acetic acid 11.36(S)-1-[2,4- Pyrrolidine-2- (2,4- 426 (MH⁺) Dimethyl- carboxylic acidDimethyl- phenoxy)- [(R)- and (S)- phenoxy) ethanoyl]-(3-chloro-phenyl)- acetyl pyrrolidine-2- cyano-methyl]- chloridecarboxylic acid amide; [1-(3-chloro- compound with phenyl)-1-cyano-trifluoro-acetic methyl]-amide acid 11.37 (S)-1-[4- Pyrrolidine-2-(4-Nitro- 455 (MH⁺) Nitro-phenyl)- carboxylic acid benzene)- butanoyl]-[(R)- and (S)- butyryl pyrrolidine-2- (3-chloro-phenyl)- chloridecarboxylic acid cyano-methyl]- [1-(3-chloro- amide; phenyl)-1-cyano-compound with methyl]-amide trifluoro-acetic acid 11.38 (S)-1-(1-Pyrrolidine-2- 2-Naph- 418 (MH⁺) Naphthalen-1- carboxylic acid thoylyl-methanoyl)- [(R)- and (S)- chloride pyrrolidine-2- (3-chloro-phenyl)-carboxylic acid cyano-methyl]- [1-(3-chloro- amide; phenyl)-1-cyano-compound with methyl]-amide trifluoro-acetic acid 11.39 (S)-1-[2-Pyrrolidine-2- (4-Meth- 428 (MH⁺) (4-Methoxy- carboxylic acid oxyl-phenoxy)- [(R)- and (S)- phenoxy)- ethanoyl]- (3-chloro-phenyl)- acetylpyrrolidine-2- cyano-methyl]- chloride carboxylic acid amide;[1-(3-chloro- compound with phenyl)-1-cyano- trifluoro-aceticmethyl]-amide acid 11.40 (S)-1-(2-Phenyl- Pyrrolidine-2- Phenyl- 408(MH⁺) ethanoyl)- carboxylic acid acetyl pyrrolidine- [(R)- and (S)-chloride 2-carboxylic acid cyano-(3,4- [1-cyano-1-(3,4-dimethoxy-phenyl)- dimethoxy- methyl]-amide; phenyl)- compound withmethyl]- trifluoro-acetic amide acid 11.41 (S)-1-[2- Pyrrolidine-2-(2-Meth- 454 (MH⁺) Methoxy- carboxylic acid oxyl- phenoxy)- [(R)- and(S)- phenoxy)- ethanoyl]- cyano-(3,4- acetyl pyrrolidine-2-dimethoxy-phenyl)- chloride carboxylic acid methyl]-amide;[1-cyano-1-(3,4- compound with dimethoxy- trifluoro-aceticphenyl)-methyl]- acid amide 11.42 (S)-1-[2-(4- Pyrrolidine-2- (4-Meth-454 (MH⁺) Methoxy- carboxylic acid oxyl- phenoxy)- [(R)- and (S)-phenoxy)- ethanoyl]- cyano-(3,4- acetyl pyrrolidine-2-dimethoxy-phenyl)- chloride carboxylic acid methyl]-amide;[1-cyano-1-(3,4- compound with dimethoxy- trifluoro-aceticphenyl)-methyl]- acid amide 11.43 (S)-1-(4- Pyrrolidine-2- Cyclo- 426(MH⁺) Cyclohexyl- carboxylic acid hexane- butanoyl)- ((R)- and (S)-butyric pyrrolidine-2- benzo[1,3] acid carboxylic acid dioxol-5-yl-chloride (1-benzo[1,3]- cyano-methyl)- dioxol-5-yl-1- amide; compoundcyano-methyl)- with trifluoro- amide acetic acid 11.44 (S)-1-{1-[1-(4-Pyrrolidine-2- 1-(4- 497 (MH⁺) Chloro-phenyl)- carboxylic acid Chloro-cyclopentyl]- [(R)- and (S)- phenyl)- methanoyl}- cyano-(3,4- 1-cyclo-pyrrolidine-2- dimethoxy-phenyl)- pentane- carboxylic acidmethyl]-amide; carboxylic [1-cyano-1-(3,4- compound acid dimethoxy- withtrifluoro- chloride phenyl)-methyl]- acetic acid amide 11.45(S)-1-((Z)-3- Pyrrolidine-2- Cinn- 420 (MH⁺) Phenyl-allanoyl)-carboxylic acid amoyl pyrrolidine-2- [(R)- and (S)- chloride carboxylicacid cyano-(3,4- [1-cyano-1-(3,4- dimethoxy-phenyl)- dimethoxy-methyl]-amide; phenyl)-methyl]- compound amide with trifluoro- aceticacid 11.46 (S)-1-(2-Phenyl- Pyrrolidine-2- (Phenyl- 440 (MH⁺) sulfanyl-carboxylic acid thio)- ethanoyl)- [(R)- and (S)- acetyl pyrrolidine-2-cyano-(3,4- chloride carboxylic acid dimethoxy-phenyl)- [1-cyano-1-(3,4-methyl]-amide; dimethoxy- compound phenyl)-methyl]- with trifluoro-amide acetic acid 11.47 (S)-1-[2-(4- Pyrrolidine-2- (4-Fluoro- 416 (MH⁺)Fluoro-phenoxy)- carboxylic acid phenoxy)- ethanoyl]- [(R)- and (S)-acetyl pyrrolidine-2- (3-chloro-phenyl)- chloride carboxylic acidcyano-methyl]- [1(3-chloro- amide; phenyl)-1-cyano- compound methyl]-with trifluoro- amide acetic acid 11.48 (S)-1-[2-(3- Pyrrolidine-2-(3-Meth- 454 (MH⁺) Methoxy- carboxylic acid oxyl- phenoxy)- [(R)- and(S)- phenoxy)- ethanoyl]- cyano-(3,4- acetyl pyrrolidine-2- dimethoxy-chloride carboxylic acid phenyl)-methyl]- [1-cyano-1-(3,4- amide;compound dimethoxy- with trifluoro- phenyl)-methyl]- acetic acid amide11.49 (S)-1-(4-Phenyl- Pyrrolidine-2- 4-Phenyl- 410 (MH⁺) butanoyl)-carboxylic acid butyryl pyrrolidine-2- [(R)- and (S)- chloridecarboxylic acid (3-chloro-phenyl)- [1-(3-chloro- cyano-methyl]-phenyl)-1-cyano- amide; compound methyl]-amide with trifluoro- aceticacid 11.50 (S)-1-[2-(3,4,5- Pyrrolidine-2- 3,4,5- 472 (MH⁺) Trimethoxy-carboxylic acid Trime- phenyl)- [(R)- and (S)- thoxy- ethanoyl]-(3-chloro-phenyl)- phenyl- pyrrolidine-2- cyano-methyl]- acetylcarboxylic acid amide; compound chloride [1-(3-chloro- withphenyl)-1-cyano- trifluoro- methyl]-amide acetic acid 11.51(S)-1-(5-Phenyl- Pyrrolidine-2- 4-Phenyl- 450 (MH⁺) pentanoyl)-carboxylic acid pentan- pyrrolidine-2- [(R)- and (S)- oicacid carboxylicacid cyano-(3,4- chloride [1-cyano-1-(3,4- dimethoxy-phenyl)- dimethoxy-methyl]-amide; phenyl)-methyl]- compound with amide trifluoro- aceticacid 11.52 (S)-1-(1-Cyclo- Pyrrolidine-2- Cyclo- 358 (MH⁺) propyl-carboxylic acid propane- methanoyl)- [(R)- and (S)- carboxy-pyrrolidine-2- cyano-(3,4- licacid carboxylic acid dimethoxy-phenyl)-chloride [1-cyano-1-(3,4- methyl]-amide; dimethoxy- compound withphenyl)-methyl]- trifluoro- amide acetic acid 11.53 (S)-1-[2-(4-Pyrrolidine-2- (4-Fluoro- 426 (MH⁺) Fluoro- carboxylic acid phenoxy)-phenoxy)- ((R)- and (S)- acetyl ethanoyl]- benzo[1,3]- chloridepyrrolidine-2- dioxol-5-yl-cyano- carboxylic acid methyl)-amide;(1-benzo[1,3]- compound with dioxol-5-yl-1- trifluoro- cyano-methyl)-acetic acid amide 11.54 (S)-1-[2-(4- Pyrrolidine-2- (4-Chloro- 433 (MH⁺)Chloro- carboxylic acid phenoxy)- phenoxy)- [(R)- and (S)- acetylethanoyl]- (3-chloro-phenyl)- chloride pyrrolidine-2- cyano- carboxylicacid methyl]-amide; [1-(3-chloro- compound with phenyl)-1- trifluoro-cyano-methyl]- acetic acid amide 11.55 (S)-1-(2-Phenyl- Pyrrolidine-2-Phenyl- 382 (MH⁺) ethanoyl)- carboxylic acid acetyl pyrrolidine- [(R)-and (S)- chloride 2-carboxylic (3-chloro-phenyl)- acid [1-(3-chloro-cyano- phenyl)-1-cyano- methyl]-amide; methyl]- compound with amidetrifluoro- acetic acid 11.56 (S)-1-(3,3- Pyrrolidine-2- 3,3-Diph- 498(MH⁺) Diphenyl- carboxylic acid enyl- propanoyl)- [(R)- and (S)-propion- pyrrolidine-2- cyano-(3,4- icacid carboyxlic aciddimethoxy-phenyl)- chloride [1-cyano-1-(3,4- methyl]-amide; dimethoxy-compound with phenyl)-methyl]- trifluoro- amide acetic acid 11.57(S)-1-[2-(3- Pyrrolidine-2- (3-Meth- 438 (MH⁺) Methoxy- carboxylic acidoxyl- phenoxy)- ((R)- and (S)- phenoxy)- ethanoyl]- benzo[1,3]- acetylpyrrolidine-2- dioxol-5-yl-cyano- chloride carboxylic acidmethyl)-amide; (1-benzo[1,3]- compound with dioxol-5-yl-1- trifluoro-cyano-methyl)- acetic acid amide 11.58 (S)-1-[2-(4- Pyrrolidine-2-(4-Ethoxy- 436 (MH⁺) Ethoxy- carboxylic acid phenyl)- phenyl)- ((R)- and(S)- acetyl ethanoyl]- benzo[1,3]- chloride pyrrolidine-2-dioxol-5-yl-cyano- carboxylic acid methyl)-amide; (1-benzo[1,3]-compound with dioxol-5-yl-1- trifluoro- cyano-methyl)- acetic acid amide11.59 (S)-1-(5- Pyrrolidine-2- 4-Phenyl- 424 (MH⁺) Phenyl- carboxylicacid pentan- pentanoyl)- [(R)- and (S)- oicacid pyrrolidine-2-(3-chloro-phenyl)- chloride carboxylic acid cyano-methyl]- [1-(3-chloro-amide; phenyl)-1-cyano- compound with methyl]-amide trifluoro- aceticacid 11.60 (S)-1-(5- Pyrrolidine-2- 4-Phenyl- 434 (MH⁺) Phenyl-carboxylic acid pentan- pentanoyl)- ((R)- and (S)- oicacidpyrrolidine-2- benzo[1,3]- chloride carboxylic acid dioxol-5-yl-cyano-(1-benzo-[1,3]- methyl)-amide; dioxol-5-yl-1- compound withcyano-methyl)- trifluoro- amide acetic acid 11.61 (S)-1-[2-(2,4-Pyrrolidine-2- (2,3- 436 (MH⁺) Dimethyl- carboxylic acid Dimethyl-phenoxy)- ((R)- and (S)- phenoxy)- ethanoyl]- benzo[1,3]- acetylpyrrolidine-2- dioxol-5-yl-cyano- chloride carboxylic acidmethyl)-amide; (1-benzo[1,3]- compound with dioxol-5-yl-1- trifluoro-cyano-methyl)- acetic acid amide 11.62 (S)-1-[2-(2- Pyrrolidine-2-(2-Meth- 438 (MH⁺) Methoxy- carboxylic acid oxyl- phenoxy)- ((R)- and(S)- phenoxy)- ethanoyl]- benzo[1,3]- acetyl pyrrolidine-2-dioxol-5-yl-cyano- chloride carboxylic acid methyl)-amide;(1-benzo[1,3]- compound with dioxol-5-yl-1- trifluoro- cyano-methyl)-acetic acid amide 11.63 (S)-1-(3- Pyrrolidine-2- Cyclo- 402 (MH⁺)Cyclohexyl- carboxylic acid hexyl- propanoyl)- [(R)- and (S)- propion-pyrrolidine-2- (3-chloro-phenyl)- icacid carboxylic acid cyano-methyl]-chloride [1-(3-chloro- amide; phenyl)-1-cyano- compound withmethyl]-amide trifluoro- acetic acid 11.64 (S)-1-[2-(3- Pyrrolidine-2-(3-Meth- 428 (MH⁺) Methoxy- carboxylic acid oxyl- phenoxy)- [(R)- and(S)- phenoxy)- ethanoyl]- (3-chloro-phenyl)- acetyl pyrrolidine-2-cyano-methyl]- chloride carboxylic acid amide; [1-(3-chloro- compoundwith phenyl)-1-cyano- trifluoro- methyl]-amide acetic acid 11.65(S)-1-[3-(2,3,4- Pyrrolidine-2- 2,3,4- 486 (MH⁺) Trimethoxy- carboxylicacid Trime- phenyl)- [(R)- and (S)- thoxy- propanoyl]-(3-chloro-phenyl)- phenyl- pyrrolidine-2- cyano-methyl]- propionylcarboxylic acid amide; chloride [1-(3-chloro- compound withphenyl)-1-cyano- trifluoro- methyl]-amide acetic acid 11.66 (S)-1-(2-Pyrrolidine-2- Benzyl- 412 (MH⁺) Benzyloxy- carboxylic acid oxyacetylethanoyl)- [(R)- and (S)- chloride pyrrolidine-2- (3-chloro-phenyl)-carboxylic cyano-methyl]- acid amide; [1-(3-chloro- compound withphenyl)-1-cyano- trifluoro- methyl]-amide acetic acid 11.67 (S)-1-(1-Pyrrolidine-2- Cyclo- 332 (MH⁺) Cyclopropyl- carboxylic acid propane-methanoyl)- [(R)- and (S)- carboxyl- pyrrolidine-2- (3-chloro-phenyl)-icacid carboxylic cyano-methyl]- chloride acid amide; [1-(3-chloro-compound with phenyl)-1-cyano- trifluoro- methyl]-amide acetic acid11.68 (S)-1-[2-(2- Pyrrolidine-2- (2-Meth- 428 (MH⁺) Methoxy- carboxylicacid oxyl- phenoxy)- [(R)- and (S)- phenoxy)- ethanoyl]-(3-chloro-phenyl)- acetyl pyrrolidine-2- cyano-methyl]- chloridecarboxylic acid amide; [1-(3-chloro- compound with phenyl)-1-cyano-trifluoro- methyl]-amide acetic acid 11.69 (S)-1-(1- Pyrrolidine-2-Cyclo- 400 (MH⁺) Cyclohexyl- carboxylic acid hexane- methanoyl)- [(R)-and (S)- carboxyl- pyrrolidine-2- cyano- icacid carboxylic acid (3,4-chloride [1-cyano-1-(3,4- dimethoxy-phenyl)- dimethoxy- methyl]-amide;phenyl)-methyl]- compound with amide trifluoro-acetic acid 11.70(S)-1-[2-(4- Pyrrolidine-2- (4-Ethoxy- 452 (MH⁺) Ethoxy-phenyl)-carboxylic acid phenyl)- ethanoyl]- [(R)- and (S)- acetyl pyrrolidine-2-cyano- chloride carboxylic acid (3,4- [1-cyano-1-(3,4-dimethoxy-phenyl)- dimethoxy- methyl]-amide; phenyl)-methyl]- compoundwith amide trifluoro-acetic acid 11.71 (S)-1-[3-(3,4,5- Pyrrolidine-2-3,4,5- 486 (MH⁺) Trimethoxy- carboxylic acid Trime- phenyl)- [(R)- and(S)- thoxy- propanoyl]- (3-chloro-phenyl)- phenyl- pyrrolidine-2-cyano-methyl]- propionyl carboxylic acid amide; compound chloride[1-(3-chloro- with trifluoro- phenyl)-1-cyano- acetic acid methyl]-amide11.72 (S)-1-(Naph- (S)-Pyrrolidine-2- Naph- 512 (MH⁺) thalene-2-carboxylic acid thalene- sulfonyl)- [1-cyano-1- 2-sulf- pyrrolidine-2-(3-phenoxy-phenyl)- onyl- carboxylic acid methyl]-amide chloride[1-cyano- 1-(3-phenoxy- phenyl)-methyl]- amide 11.73 (S)-1-(Naph-Pyrrolidine-2- Naph- 464 (MH⁺) thalene-2- carboxylic acid thalene-sulfonyl)- ((R)- and (S)- 2-sulf- pyrrolidine-2- benzo[1,3]- onyl-carboxylic acid dioxol-5-yl-cyano- chloride (1-benzo- methyl)-amide;[1,3]dioxol- compound with 5-yl-1-cyano- trifluoro-acetic methyl)-amideacid 11.74 (S)-1-(3-Cyclo- Pyrrolidine-2- Cyclo- 386 (MH⁺) pentyl-carboxylic acid pentyl- propanoyl)- [(R)- and (S)- propion-pyrrolidine-2- (3-chloro-phenyl)- icacid carboxylic acid cyano- chloride[1-(3-chloro- methyl]-amide; phenyl)-1-cyano- compound withmethyl]-amide trifluoro-acetic acid 11.75 (S)-1-(3-Cyclo- Pyrrolidine-2-Cyclo- 398 (MH⁺) pentyl- carboxylic acid pentyl- propanoyl)- ((R)- and(S)- propion- pyrrolidine-2- benzo-[1,3]- icacid carboxylic aciddioxol-5-yl-cyano- chloride (1-benzo[1,3]- methyl)-amide; dioxol-5-yl-1-compound with cyano-methyl)- trifluoro-acetic amide acid 11.76(S)-1-(3-Fluoro- Pyrrolidine-2- 3-(Fluoro- 457 (MH⁺) benzylthio-carboxylic acid benzyl)- carbamoyl)- [(R)- and (S)- isothio-pyrrolidine-2- cyano-(3,4 - cyanate carboxylic acid dimethoxy-[1-cyano-1-(3,4- phenyl)-methyl]- dimethoxy- amide; compoundphenyl)-methyl]- with trifluoro- amide acetic acid 11.77 (S)-1-[2-(2,4-Pyrrolidine-2- (2,4- 452 (MH⁺) Dimethyl- carboxylic acid Dimethyl-phenoxy)- [(R)- and (S)- phenoxy)- ethanoyl]- cyano-(3,4 - acetylpyrrolidine-2- dimethoxy- chloride carboxylic acid phenyl)-methyl]-[1-cyano-1-(3,4- amide; compound dimethoxy- with trifluoro-phenyl)-methyl] acetic acid amide

EXAMPLE A

[0317] Tablets containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per tablet Compound of formula I10.0-100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mgMagnesium stearate 1.0 mg

EXAMPLE B

[0318] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch  20.0 mg Talc  5.0 mg

EXAMPLE C

[0319] Injection solutions can have the following composition: Compoundof formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water for injectionsolutions ad 1.0 ml

[0320] Upon reading the present specification various alternativeembodiments will become obvious to the skilled artisan. These variationsare to be considered within the scope and spirit of the subjectapplication which is only to be limited to the claims that follow andtheir equivalents.

1. A compound of the formula:

wherein Y is O, S, or CH—R²; R¹ and R³ are each independently hydrogenor methyl and R² is hydrogen, or R¹ is hydrogen and R² and R³ togetherare —CH₂— thus forming a cyclopropyl ring; R⁴, R⁵ are each independentlyhydrogen or lower-alkyl; R⁶ is cycloalkyl, aryl, aryl-lower-alkyl,heteroaryl, or heteroaryl-lower-alkyl; R⁷ is —CO—R^(a), —SO₂R^(b) or—CS—NH—R^(c), wherein R^(a) is lower-alkyl, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl,aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl,arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or R^(d)—NH,R^(b) is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl,heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl, R^(c) islower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl,aryl-lower-alkyl, or heteroaryl-lower-alkyl, R^(d) is aryl-lower-alkyl;or a pharmaceutically acceptable salt or ester thereof.
 2. The compoundaccording to claim 1 , wherein R⁷ is —CO—R^(a), —SO₂—R^(b) or—CS—NH—R^(c), wherein R^(a) is lower-alkyl, cycloalkyl,cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl,aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, or R^(d)—NH, R^(b) is lower-alkyl,cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl,or aryl-lower-alkenyl, R^(c) is lower-alkyl, cycloalkyl,cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, orheteroaryl-lower-alkyl, and R^(d) is aryl-lower-alkyl.
 3. The compoundaccording to claim 1 , wherein the compound is of the formula:

wherein Y, R¹, R³, R⁴, R⁵, R⁶ and R⁷ are as defined in claim 1 .
 4. Thecompound according claim 1 , wherein Y represents CH—R² and R² is asdefined in claim 1 .
 5. The compound according to claim 4 , wherein R²is hydrogen.
 6. The compound according to claim 1 , wherein R¹ ishydrogen.
 7. The compound according to claim 1 , wherein R³ is hydrogen.8. The compound according to claim 1 , wherein R⁴ is hydrogen.
 9. Thecompound according to claim 1 , wherein R⁵ is hydrogen.
 10. The compoundaccording to claim 1 , wherein R⁶ is phenyl; furanyl; thiophenyl;pyrrolyl; phenyl substituted with alkyl, halogen, hydroxy, alkoxy,—O—(CH₂)₁₋₇—O—, aryloxy, or aryl-alkoxy; furanyl substituted with alkyl,halogen, hydroxy, alkoxy, —O—(CH₂)₁₋₇—O—, aryloxy, or aryl-alkoxy;thiophenyl substituted with alkyl, halogen, hydroxy, alkoxy,—O—(CH₂)₁₋₇—O—, aryloxy, or aryl-alkoxy; or pyrrolyl that is substitutedwith alkyl, halogen, hydroxy, alkoxy, —O— (CH₂)₁₋₇—O—, aryloxy, oraryl-alkoxy.
 11. The compound according claim 10 , wherein R⁶ is phenyl,phenyl substituted in meta-position, phenyl substituted in meta- and inpara-position, or benzo[1,3]dioxol-5-yl.
 12. The compound according toclaims 11, wherein R⁶ is 3-methoxy-phenyl, 3,4-dimethoxy-phenyl,4-benzyloxy-3-methoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, orbenzo[1,3]dioxol-5-yl.
 13. The compound according to claim 1 , whereinR⁷ is —CO—R^(a) and R^(a) is as defined in claim 1 .
 14. The compoundaccording to claim 13 , wherein R^(a) is benzyloxy,cyclopentyl-ethylene, or benzyloxy-methylene.
 15. The compound accordingto claim 13 , wherein R^(a) is 3-bromobenzyl, 4-bromobenzyl,4-chlorobenzyl, 4-fluorobenzyl, or 2-methyl-phenyloxymethylene.
 16. Thecompound according to claim 1 , wherein R⁷ is —CS—NH—R^(c) and R^(c) isas defined in claim 1 .
 17. The compound according to claim 16 , whereinR^(c) is benzyl, 3-fluorobenzyl, or furan-2-yl-methylene.
 18. Thecompounds according to claim 1 , wherein R⁷ is —SO₂—R^(b) and R^(b) isas defined in claim 1 .
 19. The compound according to claim 18 , whereinR^(b) is naphthyl.
 20. A compound of the formula:

wherein R^(6′)is aryl; R^(7′) is —CO—R^(a′) or —CS—NH—R^(c′), whereinR^(a′)is cycloalkyl-lower-alkyl, aryl-lower-alkyl, aryl-lower-alkoxy,aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, and R^(c′) isheteroaryl-lower-alkyl; or a pharmaceutically acceptable salt or esterthereof.
 21. The compound of claim 20 , wherein R^(7′)is —CO—R^(a′). 22.The compound of claim 21 , wherein R^(a′)is cycloalkyl-lower-alkyl. 23.The compound of claim 22 , wherein R^(a′)is cyclopentyl-ethyl.
 24. Thecompound of claim 23 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 25. Thecompound of claim 24 , which is(S)-1-(3-cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 26. The compound of claim21 , wherein R^(a′) is aryl-lower-alkoxy.
 27. The compound of claim 26 ,wherein R^(a′) is phenyl-methoxy.
 28. The compound of claim 27 , whereinR^(6′)is 4-benzyloxy-3-methoxy-phenyl.
 29. The compound of claim 28 ,which is (S)-2-{(R)- and(S)-[(4-benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 30. The compoundof claim 27 , wherein R^(6′)is 3-bromo-phenyl.
 31. The compound of claim30 , which is (S)-2-{(R)- and (S)-[(3-bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 32. The compoundof claim 27 , wherein R^(6′)is 3-chloro-phenyl.
 33. The compound ofclaim 32 , which is (S)-2-{(R)- and (S)-[(3-chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 34. The compoundof claim 27 , wherein R^(6′)is phenyl.
 35. The compound of claim 34 ,which is (S)-2-[(R)-(cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester.
 36. The compound of claim27 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 37. The compound of claim36 , which is (S)-2-[(R)- and(S)-(benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester.
 38. The compound of claim27 , wherein R^(6′)is 3,4-dimethoxy-phenyl.
 39. The compound of claim 38, which is (2S,3R)-2-{(R)- and (S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester.
 40. Thecompound of claim 21 , wherein R^(a) is o-tolyloxy.
 41. The compound ofclaim 40 , wherein R^(6′)is 3,4-dimethoxy-phenyl.
 42. The compound ofclaim 41 , which is(S)-1-(2-o-tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 43. The compound ofclaim 40 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 44. The compound ofclaim 43 , which is(S)-1-(2-o-tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 45. The compound ofclaim 21 , wherein R^(a′)is bromo-phenyl-methyl.
 46. The compound ofclaim 45 , wherein R^(a′)is 3-bromo-phenyl-methyl.
 47. The compound ofclaim 46 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 48. The compound ofclaim 47 , which is(S)-1-[2-(3-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 49. The compound ofclaim 46 , wherein R^(6′)is 3,4-dimethoxy-phenyl.
 50. The compound ofclaim 49 , which is(S)-1-[2-(3-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 51. The compound ofclaim 45 , wherein R^(a′)is 4-bromo-phenyl-methyl.
 52. The compound ofclaim 51 , wherein R^(6′)is 3,4-dimethoxy-phenyl.
 53. The compound ofclaim 52 , which is(S)-1-[2-(4-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 54. The compound ofclaim 51 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 55. The compound ofclaim 54 , which is(S)-1-[2-(4-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 56. The compound ofclaim 21 , wherein R^(a′) is chloro-phenyl-methyl.
 57. The compound ofclaim 56 , wherein R^(a′)is 4-chloro-phenyl-methyl.
 58. The compound ofclaim 57 , wherein R^(6′)is 3-chloro-phenyl.
 59. The compound of claim58 , which is(S)-1-[2-(4-chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 60. The compound of claim 57, wherein R^(6′)is 3,4-dimethoxy-phenyl.
 61. The compound of claim 60 ,which is (S)-1-[2-(4-chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 62. The compoundof claim 21 , wherein R^(a′)is fluoro-phenyl-methyl.
 63. The compound ofclaim 62 , wherein R^(a′)is 4-fluoro-phenyl-methyl.
 64. The compound ofclaim 63 , wherein R^(6′)is 3,4-dimethoxy-phenyl.
 65. The compound ofclaim 64 , which is(S)-1-[2-(4-fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 66. The compound ofclaim 63 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 67. The compound ofclaim 66 , which is(S)-1-[2-(4-fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 68. The compound ofclaim 21 , wherein R^(a′) is aryl-lower-alkoxy-alkyl.
 69. The compoundof claim 68 , wherein R^(a′)is phenyl-methoxy-methyl.
 70. The compoundof claim 49 , wherein R^(6′)is benzo[1,3]dioxol-5-yl.
 71. The compoundof claim 70 , which is (S)-1-benzyloxyacetyl-pyrrolidine-2-carboxylicacid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 72. Thecompound of claim 20 , wherein R^(7′) is —CS—NH—R^(c′).
 73. The compoundof claim 72 , wherein R^(c′) is furan-2yl-methyl.
 74. The compound ofclaim 73 , which is(S)-1-[(furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 75. A compoundof the formula:

wherein Y is O, S, or CH—R²; R¹ and R³ are each independently hydrogenor methyl and R² is hydrogen, or R¹ is hydrogen and R² and R³ togetherare —CH₂— thus forming a cyclopropyl ring; R⁴, R⁵ are each independentlyhydrogen or lower-alkyl; R⁶ is cycloalkyl, aryl, aryl-lower-alkyl,heteroaryl, or heteroaryl-lower-alkyl.
 76. The compound of claim 1 whichis (1RS,2RS,5SR)-2-{[(RS)- or-[(SR)-cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylicacid benzyl ester.
 77. The compound of claim 1 which is(S)-2-[(S)-(cyano-phenyl-methyl)-carbamoyl] -pyrrolidine-1-carboxylicacid benzyl ester.
 78. The compound of claim 1 which is(S)-1-(3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (R)- and(S)-(cyano-phenyl-methyl)-amide.
 79. The compound of claim 1 which is(S)-2-1(S)- and (R)-[cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 80. The compoundof claim 1 which is (S)-2-{(S)- and(R)-[cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 81. The compoundof claim 1 which is (S)-2-[(R)- and(S)-(cyano-cyclopropyl-methyl)-carbamoyl] -pyrrolidine-1-carboxylic acidbenzyl ester.
 82. The compound of claim 1 which is (R)-4-{(R)- and(S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-thiazolidine-3-carboxylic acid benzyl ester.
 83. Thecompound of claim 1 which is(S)-1-benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 84. The compound of claim1 which is (S)-1-benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)-and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 85. The compound ofclaim 1 which is (S)-1-benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 86. The compound ofclaim 1 which is(S)-1-(3-fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid [(R)-and (S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 87. The compound of claim1 which is (S)-2-((R)- and(S)-1-cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1-carboxylic acidbenzyl ester.
 88. The compound of claim 1 which is (R)-4-{(R)- and(S)-[(4-chloro-phenyl)-cyano-methyl]-carbamoyl}-thiazolidine-3-carboxylic acid benzyl ester.
 89. Thecompound of claim 1 which is (S)-2-[(R)- and(S)-(cyano-o-tolyl-methyl)-carbamoyl] -pyrrolidine-1-carboxylic acidbenzyl ester.
 90. The compound of claim 1 which is (S)-2-{(R)- and(S)-[cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 91. The compoundof claim 1 which is (S)-2-{(R)- and (S)-[cyano-(3-fluoro-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 92. The compoundof claim 1 which is (S)-2-[(R)- and(S)-(cyano-m-tolyl-methyl)-carbamoyl] -pyrrolidine-1-carboxylic acidbenzyl ester.
 93. The compound of claim 1 which is (S)-2-{(R)- and(S)-[(4-bromo-phenyl)-cyano-methyl] -carbamoyl}-pyrrolidine-1-carboxylicacid benzyl ester.
 94. The compound of claim 1 which is (S)-2-{(R)- and(S)-[cyano-(3,4,5-trimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 95. The compoundof claim 1 which is (S)-2-{(R)- and(S)-[cyano-(3-phenoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 96. The compoundof claim 1 which is(S)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 97. The compound ofclaim 1 which is (S)-1-(naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylicacid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 98. Thecompound of claim 1 which is(S)-1-(5-dimethylamino-naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl] -amide.
 99. Thecompound of claim 1 which is(S)-1-(naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 100. The compound ofclaim 1 which is (S)-1-(naphthalene-2-carbonyl)-pyrrolidine-2-carboxylicacid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 101. Thecompound of claim 1 which is(S)-1-(naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 102. The compound ofclaim 1 which is(S)-1-(3-cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 103. The compound ofclaim 1 which is (S)-1-benzyloxyacetyl-pyrrolidine-2-carboxylic acid[(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 104. Thecompound of claim 1 which is(S)-1-(naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 105. The compound of claim 1which is (S)-1-(3-cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 106. The compoundof claim 1 which is (S)-1-phenylacetyl-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 107. The compoundof claim 1 which is (S)-1-benzyloxyacetyl-pyrrolidine-2-carboxylic acid[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide.
 108. The compoundof claim 1 which is (S)-pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and(S)-(3-chloro-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide].109. The compound of claim 1 which is(S)-1-(naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-bromo-phenyl)-cyano-methyl]-amide.
 110. The compound of claim 1which is (S)-1-phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-bromo-phenyl)-cyano-methyl]-amide.
 111. The compound of claim 1which is (S)-1-benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-(3-bromo-phenyl)-cyano-methyl]-amide.
 112. The compound of claim 1which is (S)-pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and(S)-(3-bromo-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide].113. The compound of claim 1 which is(S)-1-(3-cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-methoxy-phenyl)-methyl]-amide.
 114. The compound of claim 1which is (S)-1-phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-methoxy-phenyl)-methyl]-amide.
 115. The compound of claim 1which is (S)-1-benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3-methoxy-phenyl)-methyl]-amide.
 116. The compound of claim 1which is 2-((R)- and(S)-1-cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1- carboxylic acidbenzyl ester.
 117. The compound of claim 1 which is (S)-2-{(R)- and(S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester.
 118. Thecompound of claim 1 which is(S)-1-(2-phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid ((R)- and(S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide.
 119. The compound ofclaim 1 which is (S)-pyrrolidine-1,2-dicarboxylic acid 2-{(R)- and(S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-amide}1-[(S)-(1-naphthalen-1-yl-ethyl)-amide].120. The compound of claim 1 which is(S)-1-(2-phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
 121. The compound ofclaim 1 which is(S)-1-[2-(4-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 122. The compound of claim 1which is (S)-1-[2-(4-iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 123. The compoundof claim 1 which is(S)-1-[2-(4-fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 124. The compound of claim 1which is (S)-1-(4-phenyl-butanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 125. The compound ofclaim 1 which is(S)-1-[2-(3-bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 126. The compound of claim 1which is(S)-1-(2-benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 127. The compound of claim 1which is (S)-1-(2-phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 128. The compound ofclaim 1 which is (S)-1-(2-o-tolyloxy-ethanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 129. The compound ofclaim 1 which is(S)-1-(2-benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 130. The compound ofclaim 1 which is (S)-1-(2-phenoxy-ethanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 131. The compound ofclaim 1 which is (S)-1-(2-phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 132. The compound of claim 1which is (S)-1-[2-(4-fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 133. The compoundof claim 1 which is(S)-1-(2-benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 134. The compound ofclaim 1 which is (S)-1-(3-phenyl-propanoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 135. The compoundof claim 1 which is(S)-1-[4-(3,4-dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 136. The compound ofclaim 1 which is(S)-1-[4-(3,4-dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 137. The compound of claim 1which is (S)-1-[2-(4-iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 138. The compoundof claim 1 which is(S)-1-[4-(3,4-dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 139. The compound ofclaim 1 which is(S)-1-(3-1H-indol-3-yl-propanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 140. The compound ofclaim 1 which is (S)-1-(4-phenyl-butanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 141. The compound ofclaim 1 which is(S)-1-(2-phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 142. The compound of claim 1which is (S)-1-(4-cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 143. The compound ofclaim 1 which is (S)-1-(3-cyclohexyl-propanoyl)-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 144. The compoundof claim 1 which is(S)-1-[4-(4-nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 145. The compound ofclaim 1 which is(S)-1-[2-(4-iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 146. The compound of claim 1which is(S)-1-[2-(2,4-dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 147. The compound of claim 1which is (S)-1-[4-(4-nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro -phenyl)--cyano-methyl]-amide.
 148. The compound ofclaim 1 which is(S)-1-(1-naphthalen-1-yl-methanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 149. The compound of claim 1which is (S)-1-[2-(4-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 150. The compound ofclaim 1 which is (S)-1-(2-phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 151. The compound ofclaim 1 which is(S)-1-[2-(2-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 152. The compound ofclaim 1 which is(S)-1-[2-(4-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 153. The compound ofclaim 1 which is (S)-1-(4-cyclohexyl-butanoyl)-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 154. The compoundof claim 1 which is(S)-1-{1-[1-(4-chloro-phenyl)-cyclopentyl]-methanoyl}-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 155. The compound ofclaim 1 which is (S)-1-((Z)-3-phenyl-allanoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 156. The compoundof claim 1 which is(S)-1-(2-phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 157. The compound ofclaim 1 which is(S)-1-[2-(4-fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 158. The compound of claim 1which is (S)-1-[2-(3-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 159. The compoundof claim 1 which is (S)-1-(4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 160. The compound ofclaim 1 which is(S)-1-[2-(3,4,5-trimethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 161. The compound ofclaim 1 which is (S)-1-(5-phenyl-pentanoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 162. The compoundof claim 1 which is(S)-1-(l-cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 163. The compound ofclaim 1 which is(S)-1-[2-(4-fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 164. The compound ofclaim 1 which is(S)-1-[2-(4-chloro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 165. The compound of claim 1which is (S)-1-(2-phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 166. The compound of claim 1which is (S)-1-(3,3-diphenyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 167. The compound ofclaim 1 which is(S)-1-[2-(3-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 168. The compound ofclaim 1 which is(S)-1-[2-(4-ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 169. The compound ofclaim 1 which is (S)-1-(5-phenyl-pentanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 170. The compound ofclaim 1 which is (S)-1-(5-phenyl-pentanoyl)-pyrrolidine-2-carboxylicacid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 171. The compoundof claim 1 which is(S)-1-[2-(2,4-dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 172. The compound ofclaim 1 which is(S)-1-[2-(2-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 173. The compound ofclaim 1 which is (S)-1-(3-cyclohexyl-propanoyl)-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 174. The compound ofclaim 1 which is(S)-1-[2-(3-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 175. The compound of claim 1which is (S)-1-[3-(2,3,4-trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 176. The compound of claim 1which is (S)-1-(2-benzyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 177. The compound of claim 1which is (S)-1-(1-cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 178. The compound of claim 1which is (S)-1-[2-(2-methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylicacid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 179. The compound ofclaim 1 which is (S)-1-(1-cyclohexyl-methanoyl)-pyrrolidine-2-carboxylicacid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 180. The compoundof claim 1 which is(S)-1-[2-(4-ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 181. The compound ofclaim 1 which is (S)-1-[3-(3,4,5-trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 182. The compound of claim 1which is (S)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3-phenoxy-phenyl)-methyl]-amide.
 183. The compound of claim1 which is (S)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 184. The compound ofclaim 1 which is(S)-1-(3-cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid[1-(3-chloro-phenyl)-1-cyano-methyl]-amide.
 185. The compound of claim 1which is (S)-1-(3-cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid(1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
 186. The compound ofclaim 1 which is(S)-1-(3-fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
 187. The compound ofclaim 1 which is(S)-1-[2-(2,4-dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid[1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.